Acid Base Learner Series: Respiratory Acidosis in detail

A respiratory acidosis is a primary acid-base disorder in which arterial pCO₂ rises to a level higher than expected.

At onset, the acidosis is designated as an 'acute respiratory acidosis'. The body's initial compensatory response is limited during this phase.
As the body's renal compensatory response increases over the next few days, the pH returns towards the normal value and the condition is now a 'chronic respiratory acidosis'.
The differentiation between acute and chronic
is determined by time but occurs because of the renal compensatory response (which is slow).

 Causes of Respiratory Acidosis:
The arterial pCO₂ is normally maintained at a level of about 40 mmHg by a balance between production of CO₂ by the body and its removal by alveolar ventilation. If the inspired gas contains no CO₂ then this relationship can be expressed by:

paCO₂ is proportional to V_CO2 / V_A

where:
V_CO2 is CO₂ production by the body
V_A is Alveolar ventilation

An increase in arterial pCO₂ can occur by one of three possible mechanisms:

• Presence of excess CO₂ in the inspired gas
• Decreased alveolar ventilation
• Increased production of CO₂ by the body

CO₂ gas can be added to the inspired gas or it may be present because of rebreathing : Anaesthetists are familiar with both these mechanisms. In these situations, hypercapnia can be induced even in the presence of normal alveolar ventilation and normal carbon dioxide production by the body.
An adult at rest produces about 200mls of CO₂ per minute
: this is excreted via the lungs and the arterial pCO₂ remains constant. An increased production of CO₂ would lead to a respiratory acidosis if ventilation remained constant. The system controlling arterial pCO₂ is very efficient (ie rapid and effective) and any increase in pCO₂ very promptly results in a large increase in ventilation. The result is that increased CO₂ production almost never results in respiratory acidosis. It is only in situations where ventilation is fixed that increased production will cause respiratory acidosis. Examples of this would be a ventilated patient who develops acute malignant hyperthermia: the arterial pCO₂ will rise unless the alveolar ventilation is substantially increased.

Most cases of respiratory acidosis are due to decreased alveolar ventilation.

The defect leading to this can occur at any level in the respiratory control mechanism. This provides a convenient way to classify causes that is used in the following table.

Alveolar hypoventilation may impair oxygen uptake.

The degree of arterial hypoxaemia will be related to the amount of hypoventilation. Increasing the percent of oxygen in the inspired gas can completely correct the hypoxaemia if hypoventilation is the only factor involved. If pulmonary disease leading to shunt or ventilation-perfusion mismatch is present, then the hypoxaemia will not be so easily corrected. The following list classifies causes by the mechanism or site causing the respiratory acidosis.

Causes of Respiratory Acidosis (classified by Mechanism)
A: Inadequate Alveolar Ventilation
Central Respiratory Depression & Other CNS Problems
Drug depression of resp. center (eg by opiates, sedatives, anaesthetics) CNS trauma, infarct, haemorrhage or tumour Hypoventilation of obesity (eg Pickwickian syndrome) Cervical cord trauma or lesions (at or above C4 level) High central neural blockade Poliomyelitis Tetanus Cardiac arrest with cerebral hypoxia
Nerve or Muscle Disorders
Guillain-Barre syndrome Myasthenia gravis Muscle relaxant drugs Toxins eg organophosphates, snake venom Various myopathies
Lung or Chest Wall Defects
Acute on COAD Chest trauma -flail chest, contusion, haemothorax Pneumothorax Diaphragmatic paralysis or splinting Pulmonary oedema Adult respiratory distress syndrome Restrictive lung disease Aspiration
Airway Disorders
Upper Airway obstruction Laryngospasm Bronchospasm/Asthma
External Factors
Inadequate mechanical ventilation
B: Over-production of Carbon Dioxide
Hypercatabolic Disorders
Malignant Hyperthermia
C: Increased Intake of Carbon Dioxide
Rebreathing of CO2-containing expired gas
Addition of CO2 to inspired gas
Insufflation of CO2 into body cavity (eg for laparoscopic surgery)

The generalisation made in this section is that though there are three possible distinct mechanisms that can result in a respiratory acidosis, in clinical practice, nearly all cases are due to inadequate alveolar ventilation. This is a very important point. Nevertheless the rare causes should be considered especially in Anaesthetic and Intensive Care practice where patients are often intubated and connected to circuits. Particular issues here include:

• Malignant hyperthermia (MH) is an extremely rare but potentially fatal condition which occurs almost exclusively in Anaesthetised patients exposed to certain drugs
• Various circuit misconnections & malfunctions, or soda lime exhaustion, can result in significant rebreathing of expired carbon dioxide
• Patients who are paralysed and on controlled ventilation cannot increase their alveolar ventilation to excrete any increased amounts of CO₂ produced by the body (eg in hypercatabolic states such as sepsis or MH)
• Exogenous carbon dioxide is introduced into the body in certain procedures (eg laparoscopy) and this increases the amount of carbon dioxide to be excreted by the lungs
• Adding CO₂ to the inspired gas as a respiratory stimulant has resulted, albeit rarely, in adverse outcomes in the past. (This practice is now abandoned in modern Anaesthetic practice)

Continuous capnography monitoring is now mandatory in Anaesthetic practice.

Respiratory Acidosis - Maintenance

Key Fact: A rise in arterial pCO₂ is a potent stimulus to ventilation so a respiratory acidosis will rapidly correct unless some abnormal factor is maintaining the hypoventilation.

This feedback mechanism is responsible for the normal tight control of arterial pCO₂. The factor causing the disorder is also the factor maintaining it. The prevailing arterial pCO₂ represents the balance between the effects of the primary cause and the respiratory stimulation due to the increased pCO₂.
Other then by ventilatory assistance, the pCO₂ will return to normal only by correction of the cause of the decreased alveolar ventilation.
An extremely high arterial pCO₂ has direct anaesthetic effects and this will lead to a worsening of the situation either by central depression of ventilation or as a result of loss of airway patency or protection.

Respiratory Acidosis - Metabolic Effects

Depression of Intracellular Metabolism

As CO₂ rapidly and easily crosses lipid barriers, a respiratory acidosis has rapid & generally depressing effects on intracellular metabolism.

Hypercapnia will rapidly cause an intracellular acidosis in all cells in the body. The clinical picture will be affected by the arterial hypoxaemia that is usually present. The effects described below are the metabolic effects of hypercapnia rather than respiratory acidosis. Patients with respiratory acidosis can be hypocapnic if a severe metabolic acidosis is also present.

Important effects of Hypercapnia Stimulation of ventilation via both central and peripheral chemoreceptors Cerebral vasodilation increasing cerebral blood flow and intracranial pressure Stimulation of the sympathetic nervous system resulting in tachycardia, peripheral vasoconstriction and sweating Peripheral vasodilation by direct effect on vessels Central depression at very high levels of pCO2

Importance of Cerebral Effects

The cerebral effects of hypercapnia are usually the most important.

These effects are:

• increased cerebral blood flow,
• increased intracranial pressure, &
• potent stimulation of ventilation.

This can result in dyspnoea, disorientation, acute confusion, headache, mental obtundation or even focal neurologic signs. Patients with marked elevations of arterial pCO₂ may be comatose but several factors contribute to this:

• Anaesthetic effects of very high arterial pCO₂ (eg > 100mmHg)
• Arterial hypoxaemia
• Increased intracranial pressure

As a practical clinical example, the rise in intracranial pressure due to hypercapnia may be particularly marked in patients with intracranial pathology (eg tumours, head injury) as the usual compensatory mechanism of CSF translocation may be readily exhausted. Any associated hypoxaemia will contribute to an adverse outcome.

Effects on Cardiovascular System

The effects on the cardiovascular system are a balance between the direct and indirect effects.

Typically, the patient is warm, flushed, sweaty, tachycardic and has a bouncing pulse.
The clinical picture may be modified by effects of hypoxaemia, other illnesses and the patient’s medication. Arrhythmias may be present particularly if significant hypoxaemia is present or sympathomimetics have been used.
Acutely the acidosis will cause a right shift of the oxygen dissociation curve. If the acidosis persists, a decrease in red cell 2,3 DPG occurs which shifts the curve back to the left.

An arterial pCO₂ in excess of about 90 mmHg is not compatible with life in patients breathing room air.

Why?
This is because of the obligatorily associated severe hypoxaemia. The alveolar gas equation predicts an alveolar pO₂ of 37mmHg (and the arterial pOsub>2 would be lower than this) when the pCO₂ is 90mmHg:

p_AO₂ = [0.21 x (760-47)] - 90 / 0.8 = 37 mmHg.

Higher values of paCO₂ have been recorded in patients breathing an increased inspired oxygen concentration which prevents the hypoxaemia. Values up to about 260mmHg have been recorded with inadvertent administration of high inspired pCO₂ but this is Guinness Book of Records stuff! High pCO₂ levels also have an anaesthetic effect.

Hypercapnia -vs- Respiratory acidosis? Note that 'hypercapnia' and 'respiratory acidosis' are not synonymous as, for example, a patient with a severe metabolic acidosis and a concomitant respiratory acidosis could have an arterial pCO2 less than 40mmHg. However, most of the discussion of 'metabolic effects' on this page is more correctly the 'metabolic effects of hypercapnia' rather than respiratory acidosis per se. Despite this, even in the mixed disorder just mentioned, the effects of an elevated arterial pCO2 are linear, so compared to the situation of a severe metabolic acidosis alone, the metabolic effects of the higher pCO2 of the mixed acid-base disorder (ie with the concomitant respiratory acidosis) are mostly still relatively correct. Respiratory Acidosis - Compensation The compensatory response is a rise in the bicarbonate level This rise has an immediate component (due to a resetting of the physicochemical equilibrium point) which raises the bicarbonate slightly. Next is a slower component where a further rise in plasma bicarbonate due to enhanced renal retention of bicarbonate. The additional effect on plasma bicarbonate of the renal retention is what converts an "acute" respiratory acidsosis into a "chronic" respiratory acidosis. As can be seen by inspection of the Henderson-Hasselbalch equation (below), an increased [HCO3-] will counteract the effect (on the pH) of an increased pCO2 because it returns the value of the [HCO3]/0.03 pCO2 ratio towards normal. pH = pKa + log([HCO3]/0.03 pCO2) Buffering in Acute Respiratory Acidosis The compensatory response to an acute respiratory acidosis is limited to buffering. By the law of mass action, the increased arterial pCO2 causes a shift to the right in the following reaction: CO2 + H2O <-> H2CO3 <-> H+ + HCO3- In the blood, this reaction occurs rapidly inside red blood cells because of the presence of carbonic anhydrase. The hydrogen ion produced is buffered by intracellular proteins and by phosphates. Consequently, in the red cell, the buffering is mostly by haemoglobin. This buffering by removal of hydrogen ion, pulls the reaction to the right resulting in an increased bicarbonate production. The bicarbonate exchanges for chloride ion across the erythrocyte membrane and the plasma bicarbonate level rises. In an acute acidosis, there is insufficient time for the kidneys to respond to the increased arterial pCO2 so this is the only cause of the increased plasma bicarbonate in this early phase. The increase in bicarbonate only partially returns the extracellular pH towards normal. Empirically, the [HCO3-] rises by 1 mmol/l for every 10mmHg increase in pCO2 above its reference value of 40mmHg. For example, if arterial pCO2 has risen acutely from 40mmHg to 60mmHg (due to decreased alveolar ventilaton) then this acute rise of 2 tens (i.e. 60-40=20mmHg rise) results in a rise of plasma bicarbonate by 2 from its reference value of 24mmol/l up to 26 mmol/l. Consequently, we would predict that if this acute respiratory acidosis was the only base disorder present, then plasma bicarbonate would be 26mmol/l. Though very important for carriage of carbon dioxide in the blood, the bicarbonate system is not itself responsible for any buffering of a respiratory acid-base disorder. This is because a system cannot buffer itself. If HCO3 were to react with H+ produced from the dissociation of H2CO3 this would just produce H2CO3 again - reversing the reaction is not 'buffering'. Ninety-nine percent of the buffering of an acute respiratory acidosis occurs intracellularly. Proteins (especially haemoglobin in red cells) and phosphates are the most important buffers involved. These take up the H+ produced from the dissociation of H2CO3. This intracellular buffering results in a further increase in intracellular [HCO3] because it pulls the CO2 hydration reaction to the right. The HCO3 that leaves the cell causes the rise in extracellular HCO3. The amount of buffering is limited by the concentration of protein as that is low relative to the amount of carbon dioxide requiring buffering. In summary: Compensation for an acute respiratory acidosis is by intracellular buffering and plasma bicarbonate rises slightly as a result of this buffering. The buffering is predominantly due to intracellular proteins; the bicarbonate system does not contribute to this buffering. Chronic Respiratory Acidosis: Renal Bicarbonate Retention With continuation of the acidosis, the kidneys respond by retaining bicarbonate. If the respiratory acidosis persists then the plasma bicarbonate rises to an even higher level because of renal retention of bicarbonate. Thus in a chronic respiratory acidosis there are TWO factors present which elevate the plasma bicarbonate:- Firstly: The acute physicochemical change and consequent buffering esp by intracellular protein. (Immediate onset - as occurs with an acute respiratory acidosis.) Secondly: The renal retention of bicarbonate as renal function is altered by the elevated arterial pCO2 and additional bicarbonate is added to the blood passing through the kidney. (Slow onset) Studies have shown that an average 4 mmol/l increase in [HCO3-] occurs for every 10mmHg increase in pCO2 from the reference value of 40mmHg. For example, if arterial pCO2 has risen from 40mmHg to 60mmHg (due to decreased alveolar ventilaton) and remained elevated for several days, then this chronic rise of "2 tens" (i.e. 60-40=20mmHg rise = 2 rises of 10mmHg) results in a rise of plasma bicarbonate by 8 from its reference value of 24mmol/l up to 32 mmol/l. Consequently, we would predict that if this chronic respiratory acidosis was the only base disorder present, then plasma bicarbonate would be 32mmol/l. The renal response in underway by 6 to 12 hours with a maximal effect reached by 3 to 4 days. This maximal effect is not sufficient to return plasma pH to normal, but because of the additional renal contribution, the pH is returned towards normal much more than occurs in an acute respiratory acidosis. The response occurs because increased arterial pCO2 increases intracellular pCO2 in proximal tubular cells and this causes increased H+ secretion from the PCT cells into the tubular lumen. This results in: increased HCO3 production which crosses the basolateral membrane and enters the circulation (so plasma [HCO3] increases.) increased Na+ reabsorption in exchange for H+ and less in exchange for Cl- (so plasma [Cl-] falls) increased 'NH3' production to 'buffer' the H+ in the tubular lumen (so urinary excretion of NH4Cl increases) 'Maximal compensation' versus 'full compensation'?. The increase in plasma [HCO3] results in an increase in amount of bicarbonate filtered in the kidney and this amount increases as plasma bicarbonate continues to increase. Eventually a new steady state is reached which is referred to as ‘maximal compensation’. This level of compensation has long been believed to be less than that required to return the plasma pH to normal. That is the actual compensation ('maximal compensation') is less than 'full compensation'. If the pH was found to actually be within the normal range, the interpretation of this was that there was a co-existing metabolic alkalosis (e.g. due to use of diuretics or corticosteroids) or there had been transient hyperventilation from the stress of arterial puncture. A recent study1 examined the actual maximal response in a group of patients with stable chronic hypercapnic respiratory failure without a clinical condition or medications those could cause a metabolic alkalosis. The majority of these patients had pH values in the normal range as the compensation was greater than that predicted by the classic 4 for 10 rule. They found that bicarbonate increased by 5.1 mmols/l for every 10mmHg pCO2 rise. Consequently, a diagnosis of mild metabolic alkalosis should not be made in patients with stable chronic respiratory acidosis with pH values in the normal range unless there is other evidence (e.g. use of thiazide or loop diuretics, or corticosteroids) consistent with the diagnosis. In summary, the compensation for hypercapnia is: Acute: Buffering only and predominantly intracellular (99%) Chronic: Renal retention of bicarbonate (in addition to buffering) Summary notes about the compensation terms Maximal compensation refers to the actual maximal amount of compensation that is typically seen in a patient with a simple acid-base disorder. Full compensation refers to the amount of compensation that would correct the pH all the way back to within the normal range. The general rule for all acid-base disorders is that the body's compensatory response is almost never sufficient to return the plasma pH to normal. If the pH is normal then it suggests that a second, compensating acid-base disorder is present. Contrary to this 'classic' teaching, a recent paper1 suggests that in many patients with chronic stable hypercapnia, compensation may be sufficient to return pH to within the normal range. Differing time courses of compensation and correction The situation may be complicated because of the differing time courses of compensation & correction. Consider a couple of typical situations which sometimes cause confusion in interpretation: Scenario 1 Correction of a chronic respiratory acidosis can occur more rapidly than correction of the renal compensation so it is possible that the blood gases in an individual patient may appear to show 'full compensation' if the alveolar ventilation has increased and before the kidneys have had time to adjust. The stimulation of being in the Emergency Room may result in such a situation and the snapshot provided by a single set of gases may reveal such a situation. (Remember this when the junior doctor alights upon such a set of results and says, "But I thought you said that compensation never 'fully' returns the pH to normal but this is what has happened here?") Scenario 2 If a patient with chronic respiratory acidosis is intubated and ventilated, the arterial pCO2 can be rapidly corrected (by adjusting the ventilator parameters). This can occur quite rapidly, but the elevated bicarbonate takes longer longer than this to fall. The situation can be more complicated because some such patients have additional factors which inhibit the ready excretion of the elevated bicarbonate, as occurs in 'post-hypercapnic metabolic alkalosis'.) References Martinu T, Menzies D, and Dial S. Re-evaluation of acid-base prediction rules in patients with chronic respiratory acidosis. Can Respir J 2003 Sep; 10(6) 311-5. PubMed [See also the accompanying editorial]  Respiratory Acidosis - Correction Restoration of Adequate Alveolar Ventilation The pCO2 rapidly returns to normal with restoration of adequate alveolar ventilation Treatment usually needs to be directed to correction of the primary cause if this is possible. In severe cases, intubation and mechanical ventilation will be necessary to restore alveolar ventilation. The patient can deteriorate following intubation and ventilation which results in a rapid fall in pCO2 especially if the respiratory acidosis has been present for some time. This became apparent when mechanical ventilation was instituted in the chronically hypercapnic patients during the polio epidemic in Copenhagen in about 1950. Rapid return of pCO2 towards normal was often accompanied by severe hypotension. The sympathetic stimulation due to prolonged hypercapnia resulted in patients who were relatively vasoconstricted and volume depleted. 'Post hypercapnic alkalosis' (see below) may also contribute to the pathophysiology due to decreased myocardial contractility. The net result of such rapid correction of arterial pCO2 was hypotension. These patients required significant fluid loading. (Incidentally, this epidemic and the experience in ventilating large numbers of patients resulted in the birth of ‘Respiratory Units’ which gradually evolved into the Intensive Care Unit of today. See Pontoppidan H et al. Respiratory Intensive Care. Anesthesiology. 1977; 47: 96-116 for more details) In some other situations, it is preferable not to return arterial pCO2 to 40 mmHg with mechanical ventilation eg in patients with chronic CO2 retention from severe chronic obstructive airways disease. In some asthmatics presenting with severe bronchospasm (but not respiratory arrest), the problems associated with ventilation in this situation may suggest that administration of high oxygen concentrations to prevent hypoxaemia and tolerance of significant hypercapnia (‘permissive hypercapnia’) is a beneficial strategy. The idea is to adjust ventilation to allow adequate oxygenation using lower inspiratory pressures and so decrease the risk of barotrauma. What is ‘post hypercapnic alkalosis’? If a chronically elevvated arterial pCO2 is returned to normal relatively quickly (as can happen if the patient is intubated and ventilated), then the patient is in the situation of having an elevated bicarbonate (due renal compensation) without there being the physiological need for it anymore. The elevated bicarbonate is typically slow to fall as return to normal requires renal excretion of the excess bicarbonate. The kidney normally has a large capacity to excrete bicarbonate but several factors, particularly chloride depletion, impairs this. Consequently, the bicarbonate level can remain persistently elevated; this state is referred to as ‘post-hypercapnic alkalosis’. The general factors causing maintenance of high bicarbonate levels in this situation are the same as those involved in maintenance of a metabolic alkalosis. These factors are chloride depletion, potassium depletion, ECF volume depletion and reduction of GFR. This situation occurs almost exclusively in ICU patients with chronic hypercapnia who are acutely ventilated back towards a normal arterial pCO2. Chloride depletion occurring during the hypercapnia is probably the most important factor involved in the maintenance of the high bicarbonate levels. These complex patients may also have other disorders which can themselves cause a metabolic alkalosis. In particular, the use of diuretics and loss of acidic gastric secretions (by nasogastric drainage) can be important factors in causing chloride depletion. Even with use of of H2-blockers (such as ranitidine), high nasogastric drainage can still result in significant chloride losses. These patients are often avidly retaining sodium in the kidneys and in the presence of low chloride levels, this is associated with high levels of bicarbonate re absorption. In general, bicarbonate levels in this situation are in the 30 to 45 mmol/l range. Correction of fluid and chloride depletion leads to a fall in plasma bicarbonate levels. References Banga A and Khilnani GC. Post-hypercapnic alkalosis is associated with ventilator dependence and increased ICU stay. COPD. 2009; 6: 437-440. Pubmed Respiratory Acidosis Correction: Some causes are not amenable to preventive measures. Monitoring of at-risk patients with capnography is appropriate in some situations (eg in an Intensive Care Unit, intraoperatively and in the Recovery Room) and will allow earlier detection of a problem. The end-tidal pCO2 is typically lower than the arterial pCO2 and the difference between these values is an index of the magnitude of the alveolar dead space. So if the end-tidal pCO2 is elevated then the arterial pCO2 is usually even more elevated. First Key Fact: Watch for inadequate alveolar ventilation Inadequate alveolar ventilation is the underlying problem in nearly all patients so any patient who could have impaired ventilation is at risk of developing respiratory acidosis. So recognise these at-risk situations. Second Key Fact: Give oxygen to avoid hypoxaemia Inadequate ventilation will also necessarily affect arterial oxygenation so steps to avoid, recognise and/or treat arterial hypoxaemia are very important. The simple measure of providing supplemental oxygen by face mask to patients can often correct or prevent hypoxaemia. Some particular medical situations where prevention can be utilised are: Better airway care and attention to safe positioning of cerebrally obtunded patients (ie prevent airway obstruction). Increased care in the use of drugs (such as CNS sedatives or opiate drugs) which can depress ventilation Increased attention to the care of patients at risk of aspiration (eg unconscious patients) Ensuring adequate reversal of neuromuscular relaxants         Credit: Kerry Brandis