Respiratory Alkalosis

Respiratory alkalosis is a condition of elevated blood pH resulting from excessive alveolar ventilation that leads to a decrease in arterial carbon dioxide (PaCO₂) below normal levels.

Exam domain	One-glance essentials
Definition / diagnosis	*Primary hyperventilation lowers pCO₂ and raises pH* ^[1] Acute: pH > 7.45, pCO₂ < 35 mmHg; chronic renal HCO₃⁻ loss may fully normalise pH ^[1]^[2]
Epidemiology / risks	PE, pneumonia/hypoxaemia, sepsis, liver failure, pregnancy and CNS disease stimulate ventilation ^[2] Salicylates, anxiety/pain and excessive mechanical ventilation are classic causes ^[2]^[3]
Core mechanism	CO₂ washout lowers H⁺; acute buffering and later renal HCO₃⁻ excretion compensate ^[1] Hypocapnia causes cerebral/coronary vasoconstriction, while alkalinaemia lowers ionised Ca²⁺ and shifts K⁺ intracellularly ^[2]
Clinical picture	Light-headedness, perioral/limb paraesthesiae, carpopedal spasm and syncope are typical ^[2] Tachypnoea with hypoxaemia, fever, chest pain or neurological signs suggests dangerous secondary disease, not anxiety ^[2]
Investigations	*ABG: low pCO₂ with alkalinaemia or chronic compensated normal pH; check expected HCO₃⁻ compensation* ^[1]^[2] A–a gradient separates pulmonary causes (raised) from many extrapulmonary causes (normal) ^[2] Calculate AG and check salicylate level when unexplained; mixed respiratory alkalosis + HAGMA is classic ^[3]
Management	Treat the driver: oxygen and pulmonary treatment for hypoxia, sepsis therapy, ventilator adjustment, analgesia/anxiety care ^[2] Salicylate poisoning → *activated charcoal + bicarbonate alkalinisation; haemodialysis when severe* ^[3] Symptomatic tetany or significant hypokalaemia → targeted calcium/K⁺ replacement ^[2]
Complications	Cerebral hypoperfusion → confusion, syncope or seizures; low ionised Ca²⁺ → tetany ^[2] Hypokalaemia/low ionised Ca²⁺ may prolong QT and cause arrhythmia ^[2]
Prevention / follow-up	Avoid excessive ventilator minute ventilation; reassess blood gas after adjustments ^[2] Control recurrent pulmonary, hepatic, toxicological or anxiety triggers rather than repeatedly treating the pH ^[2]
Exam traps	*Never label tachypnoea as psychogenic before excluding PE, sepsis, pneumothorax and metabolic acidosis* ^[2] In salicylate toxicity, do not suppress compensatory hyperventilation; abrupt pCO₂ rise increases CNS salicylate entry ^[3] In acute asthma, a rising/normal pCO₂ may signal respiratory fatigue, not improvement ^[2]

References

^[1] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf ^[2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p.2–3); MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.92); Ryan Ho Fundamentals.pdf (p.230) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (p.42, Salicylate poisoning); Ryan Ho Urogenital.pdf (p.48, Aspirin toxicity treatment)

Respiratory alkalosis is a primary acid-base disorder characterised by a decrease in arterial partial pressure of carbon dioxide (pCO₂) resulting from alveolar hyperventilation that exceeds the body's metabolic CO₂ production. This drives the arterial pH upward (towards alkalinity).

Respiratory alkalosis = hyperventilation → ↓pCO₂ → shifts pH up ^[1]^[2]
Alkalosis = an ongoing process causing removal of plasma [H⁺]; alkalaemia = arterial pH > 7.45, the result when compensation is insufficient ^[1]^[2]
A patient can have respiratory alkalosis without alkalaemia if metabolic compensation is adequate — this is the key distinction between the process (alkalosis) and the end-result (alkalaemia)

Breaking down the terminology:

"Respiratory" → the primary derangement is in the respiratory (CO₂) component of the Henderson-Hasselbalch equation
"Alkalosis" → from Arabic al-qalī (ashes of a plant), referring to basic/alkaline; the process drives pH upward

The Henderson-Hasselbalch Equation — First Principles

$\text{pH} \propto \frac{[\text{HCO}_3^-]}{[\text{CO}_2]}$

Mnemonic: Acidity = Bicarb / Carbon dioxide (A = B/CD) ^[2]

In respiratory alkalosis, the denominator (CO₂) falls because the lungs blow off CO₂ faster than metabolism produces it → the ratio rises → pH rises
The metabolic component is represented by HCO₃⁻ concentration; the respiratory component is represented by CO₂ concentration ^[2]
Normal pH is 7.4 (range 7.35–7.45), corresponding to [H⁺] of 40 nmol/L ^[1]
Lethal pH levels: < 7.1 or > 7.7 — all cellular function becomes disrupted ^[1]

High Yield — Compensation in Respiratory Alkalosis

Compensation for primary respiratory alkalosis = compensatory metabolic acidosis → kidney excretes more HCO₃⁻ → reduced [HCO₃⁻] ^[1]^[2]

Respiratory compensation occurs immediately and reaches maximum in 12 hours ^[2]
Metabolic compensation occurs via: (1) acute buffering (modest) and (2) chronic renal HCO₃⁻ excretion (significant, takes several days) ^[2]
Rule of thumb: ONLY in chronic respiratory alkalosis may there be complete compensation (i.e. normal pH) ^[1]^[2] — This is the one acid-base disorder where full compensation back to normal pH is expected. In all other primary acid-base disturbances, compensation is incomplete.

Why is chronic respiratory alkalosis the only disorder with complete compensation? Because the kidney can very effectively dump bicarbonate when given enough time (days). The sustained low pCO₂ reduces proximal tubular HCO₃⁻ reabsorption (less CO₂ available for intracellular carbonic anhydrase → less H⁺ secretion → less HCO₃⁻ reclaimed) and reduces distal nephron H⁺ secretion. The net effect is a substantial reduction in serum HCO₃⁻ that can fully normalise the HCO₃⁻/CO₂ ratio, restoring pH to ~7.40. Other acid-base disorders cannot fully compensate because their compensatory mechanisms have inherent limitations (e.g., you can't hypoventilate indefinitely because hypoxia limits it).

Respiratory alkalosis is the most common acid-base disturbance encountered in hospitalised patients ^[3]
- Why? Because many common hospital conditions (pain, anxiety, sepsis, pneumonia, PE, mechanical ventilation) all drive hyperventilation
It is also very common in the community — anxiety-related hyperventilation is frequent in young adults
In Hong Kong, relevant epidemiological considerations:
- High prevalence of anxiety disorders in the urban population → psychogenic hyperventilation
- High burden of pneumonia (especially in the elderly, and during influenza/COVID-19 seasons) → hypoxia-driven hyperventilation
- Significant prevalence of chronic liver disease (hepatitis B carrier rate ~7–8% of the population) → hepatic encephalopathy/liver failure commonly causes a respiratory alkalosis
- Sepsis in ICU patients — respiratory alkalosis is often the earliest laboratory finding in gram-negative sepsis
- High-altitude exposure is less relevant in HK itself but important for travellers (e.g., trips to Tibet/Nepal)
No significant sex or ethnic predilection for respiratory alkalosis per se — it depends on the underlying cause
Age distribution: any age, but the cause profile differs:
- Young adults: anxiety, hyperventilation syndrome, salicylate poisoning
- Elderly: pneumonia, PE, sepsis, heart failure, liver failure

Risk factors are essentially the conditions that predispose to hyperventilation:

Category	Risk Factors
Pulmonary	Pneumonia, asthma, PE, interstitial lung disease, early ARDS
Cardiovascular	Congestive heart failure, severe anaemia
Hepatic	Chronic liver disease (HBV/HCV cirrhosis — very relevant in HK), acute liver failure
CNS	Stroke, meningitis/encephalitis, brain tumours, traumatic brain injury
Metabolic/Endocrine	Sepsis/SIRS, thyrotoxicosis, pregnancy (progesterone effect)
Drug/Toxin	Salicylate poisoning, progesterone, methylxanthines (theophylline, caffeine), catecholamines
Psychogenic	Anxiety disorders, panic disorder, pain
Iatrogenic	Mechanical ventilation (over-ventilation — excessive tidal volume or respiratory rate set too high)
Environmental	High altitude (> 2500 m)
Pregnancy	Normal pregnancy (progesterone stimulates respiratory centre → chronic mild respiratory alkalosis is physiological in pregnancy)

Anatomy and Physiology of CO₂ Homeostasis

To understand respiratory alkalosis from first principles, you need to understand how CO₂ is regulated:

CO₂ is a byproduct of aerobic cellular metabolism (Krebs cycle)
Normal CO₂ production: ~200 mL/min at rest
CO₂ is transported in blood in three forms:
1. Dissolved CO₂ (~5–10%)
2. Carbaminohaemoglobin (~20–30%) — bound to Hb
3. Bicarbonate (~60–70%) — via the reaction: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻ (catalysed by carbonic anhydrase in RBCs)

CO₂ is eliminated entirely through the lungs
Alveolar ventilation (V_A) is the key determinant of pCO₂:

$pCO_2 \propto \frac{\text{CO}_2 \text{ production (VCO}_2\text{)}}{\text{Alveolar ventilation (V}_A\text{)}}$

Therefore: ↑V_A → ↓pCO₂ → respiratory alkalosis
Minute ventilation = Tidal volume × Respiratory rate; but only the alveolar portion matters (dead space ventilation is wasted)

Medullary respiratory centre (dorsal and ventral respiratory groups): generates rhythmic breathing
Central chemoreceptors (ventral medulla): respond to CSF pH (which closely reflects pCO₂ because CO₂ freely crosses the blood-brain barrier)
- ↑pCO₂ → ↓CSF pH → stimulates ventilation
- ↓pCO₂ → ↑CSF pH → reduces ventilatory drive (this is the brake that normally prevents excessive CO₂ washout)
Peripheral chemoreceptors (carotid body, aortic body): respond primarily to ↓pO₂ (also ↑pCO₂ and ↓pH)
- Activated when pO₂ < ~60 mmHg → stimulates hyperventilation
Higher cortical centres: can override the brainstem → voluntary hyperventilation (anxiety, pain)
Pulmonary J-receptors (juxtacapillary receptors): stimulated by interstitial oedema, pulmonary congestion, microemboli → reflex tachypnoea/hyperventilation

The kidney compensates for respiratory alkalosis by excreting more HCO₃⁻ and reducing H⁺ excretion ^[1]^[2]
Acute phase (minutes to hours): buffering by intracellular buffers (proteins, haemoglobin, phosphate); H⁺ shifts out of cells in exchange for K⁺ and Na⁺; HCO₃⁻ drops modestly (~2 mEq/L per 10 mmHg drop in pCO₂)
Chronic phase (2–5 days): kidney reduces proximal tubular HCO₃⁻ reabsorption and distal H⁺ secretion; HCO₃⁻ drops more substantially (~4–5 mEq/L per 10 mmHg drop in pCO₂)

Etiology (with Focus on Hong Kong Context)

The causes of respiratory alkalosis are best organised by the mechanism of hyperventilation:

Detailed Etiological Categories

When pO₂ falls < ~60 mmHg, carotid body chemoreceptors fire → ↑ventilation → pCO₂ drops

Cause	HK Relevance & Pathophysiology
Pneumonia	Very common in HK (bacterial, viral including influenza and COVID-19). V/Q mismatch and shunt → hypoxaemia → hyperventilation
Pulmonary embolism	Significant cause. Dead space ↑, V/Q mismatch → hypoxaemia; also J-receptor stimulation by microemboli
Interstitial lung disease	Diffusion impairment → hypoxaemia, especially on exertion
Asthma (early/moderate)	Airway obstruction with preserved drive → hyperventilation of unaffected alveoli → ↓pCO₂ (late severe asthma → T2RF with ↑pCO₂)
High altitude	Less relevant within HK but important for travellers to Tibet/Nepal
Severe anaemia	Reduced O₂ carrying capacity → tissue hypoxia → ↑ventilatory drive
R-to-L cardiac shunts	Deoxygenated blood bypasses lungs → systemic hypoxaemia

Cause	HK Relevance & Pathophysiology
Sepsis / SIRS	Extremely important — respiratory alkalosis is often the earliest sign of sepsis, even before fever. Endotoxins and cytokines (IL-1, TNF-α) directly stimulate the medullary respiratory centre. Gram-negative organisms are classic
Hepatic failure / Cirrhosis	Very relevant in HK given high HBV prevalence. Mechanism: ↑circulating toxins (ammonia, progesterone, endogenous benzodiazepine-like substances) stimulate the respiratory centre; portosystemic shunting allows these to bypass liver detoxification
CNS pathology	Stroke (especially brainstem), meningitis/encephalitis, brain tumours, head trauma — direct irritation of respiratory centres
Salicylate (aspirin) poisoning	Direct stimulation of medullary respiratory centre (this is why salicylate toxicity classically gives a mixed acid-base picture: respiratory alkalosis and metabolic acidosis simultaneously)
Progesterone	Stimulates central ventilatory drive; explains physiological respiratory alkalosis of pregnancy (pCO₂ drops to ~30 mmHg in normal pregnancy)
Methylxanthines	Theophylline, caffeine — stimulate respiratory centre
Thyrotoxicosis	↑metabolic rate → ↑CO₂ production + direct central stimulation of ventilation

High Yield — Salicylate Poisoning and Acid-Base

Salicylate poisoning produces a characteristic mixed disturbance: early respiratory alkalosis (direct stimulation of respiratory centre) + later metabolic acidosis (uncoupling of oxidative phosphorylation, accumulation of organic acids). In adults the respiratory alkalosis often predominates initially; in children the metabolic acidosis tends to be more prominent. This is a favourite exam question.

Cause	Pathophysiology
Heart failure (pulmonary congestion)	Pulmonary oedema stimulates J-receptors → reflex tachypnoea/hyperventilation. Also contributes to hypoxaemia via shunting
Pulmonary embolism	J-receptors activated by microemboli and pulmonary infarction; also V/Q mismatch → hypoxaemia
Pneumothorax	Stimulation of lung receptors + hypoxaemia

Cause	Notes
Anxiety / Panic disorder	Very common, especially in young adults. Cortical override of brainstem centres. Often presents dramatically with paraesthesias, carpopedal spasm — the "hyperventilation syndrome"
Pain	Acute pain drives hyperventilation via cortical and limbic inputs
Voluntary hyperventilation	Rare as a sustained cause; used in provocative testing

Cause	Notes
Mechanical over-ventilation	Common ICU problem — excessive tidal volume or respiratory rate on ventilator → ↓pCO₂. Must monitor ABG and adjust settings

Pregnancy (normal physiological state — chronic respiratory alkalosis with pCO₂ ~28–32 mmHg, fully compensated)
Fever (↑metabolic rate → ↑CO₂ production, but ventilatory response overshoots)
Heat stroke
Recovery phase of metabolic acidosis (ventilatory drive persists after acidosis corrected → transient respiratory alkalosis)

Classification

Respiratory alkalosis is classified by chronicity, which determines the degree of compensation:

Duration: minutes to hours (< 24–48 hours)
Compensation: only cellular buffering (H⁺ released from intracellular buffers, modest)
- Expected: HCO₃⁻ drops by ~2 mEq/L for every 10 mmHg fall in pCO₂ ^[3]
- Minimum HCO₃⁻ typically does not fall below ~18 mEq/L
pH is elevated (incomplete compensation) — frank alkalaemia

Duration: > 2–5 days
Compensation: renal HCO₃⁻ excretion (substantial)
- Expected: HCO₃⁻ drops by ~4–5 mEq/L for every 10 mmHg fall in pCO₂ ^[3]
- Minimum HCO₃⁻ may drop to ~12–15 mEq/L
pH may be completely normal — the only acid-base disorder where this occurs ^[1]^[2]

Parameter	Acute Resp Alkalosis	Chronic Resp Alkalosis
pCO₂	↓↓	↓↓
HCO₃⁻	Mildly ↓ (buffering only)	Significantly ↓ (renal excretion)
pH	↑ (alkalaemic)	Normal or near-normal
Expected compensation	ΔHCO₃⁻ = 2 × (ΔpCO₂/10)	ΔHCO₃⁻ = 4–5 × (ΔpCO₂/10)

Exam Trap — Normal pH with Low pCO₂

A normal pH with low pCO₂ and low HCO₃⁻ could be:

Fully compensated chronic respiratory alkalosis (most common interpretation)
Mixed metabolic acidosis + respiratory alkalosis (the two derangements cancel each other's pH effects)

You must use the clinical context to distinguish. If the patient has chronic liver disease and a stable low pCO₂ for weeks, it's chronic respiratory alkalosis. If the patient has sepsis with lactic acidosis AND tachypnoea, it could be a mixed disorder.

Clinical Features

The symptoms of respiratory alkalosis arise from two main mechanisms:

Alkalosis → ↓ionised calcium (Ca²⁺ binds more to albumin at higher pH)
↓pCO₂ → cerebral vasoconstriction (CO₂ is a potent cerebral vasodilator; losing it constricts cerebral vessels)
Hypokalaemia (alkalosis shifts K⁺ intracellularly)

Symptom	Mechanism
Lightheadedness / Dizziness	↓pCO₂ → cerebral vasoconstriction → ↓cerebral blood flow (can drop by 35–40% with pCO₂ around 20 mmHg)
Confusion / Impaired concentration	Same mechanism: cerebral hypoperfusion
Syncope / Pre-syncope	Severe cerebral vasoconstriction can cause transient loss of consciousness
Perioral numbness and paraesthesias (especially circumoral + fingers/toes)	Alkalosis → ↑albumin-Ca²⁺ binding → ↓ionised [Ca²⁺] ^[4] — reduced ionised calcium increases neuronal excitability. Sensory neurons fire spontaneously → tingling and numbness
Carpopedal spasm (tetany)	Same mechanism: ↓ionised Ca²⁺ → neuromuscular hyperexcitability → involuntary muscle contraction of hands ("main d'accoucheur" — obstetrician's hand appearance) and feet ^[4]
Muscle cramps	↓ionised Ca²⁺ + ↓K⁺ → muscle hyperexcitability
Chest tightness / Dyspnoea	Often the initial complaint that drives the patient to hyperventilate further (especially in anxiety); also bronchoconstriction from hypocapnia
Palpitations	↓K⁺ shift intracellularly (alkalosis → ↓ECF [K⁺] ^[5]) + sympathetic activation → arrhythmia substrate
Dry mouth	Mouth breathing during hyperventilation
Anxiety / Sense of doom	Often the cause (psychogenic hyperventilation), but also perpetuated by the symptoms → vicious cycle (cognitive theory: anxiety → physical symptoms → ↑anxiety ^[6])
Blurred vision	Cerebral vasoconstriction affecting visual cortex perfusion
Nausea	Cerebral hypoperfusion

Why Does Alkalosis Cause Hypocalcaemia Symptoms?

Alkalosis (including acute respiratory alkalosis from hyperventilation) causes ↓ionised calcium ^[4]. The total serum calcium may be completely normal. Here's why:

At higher pH, albumin becomes more negatively charged (H⁺ dissociates from albumin carboxyl groups) → more Ca²⁺ binds to albumin → the free/ionised fraction drops. Since it's the ionised Ca²⁺ that determines neuromuscular excitability, patients develop symptoms of hypocalcaemia (paraesthesias, tetany) even with a normal total calcium.

This is why checking ionised calcium (not just total calcium) is important in alkalotic patients.

Sign	Mechanism
Tachypnoea / Hyperpnoea	The fundamental cause: increased rate and/or depth of breathing. This IS the hyperventilation
↓pCO₂ on ABG	Direct consequence of alveolar hyperventilation
Chvostek's sign (tapping CN VII → facial twitching)	↓ionised Ca²⁺ → neural hyperexcitability → facial nerve fires with minimal stimulation ^[4]
Trousseau's sign (BP cuff inflation > systolic BP for 3 min → carpopedal spasm)	↓ionised Ca²⁺ → latent tetany unmasked by ischaemia (cuff occludes arterial flow → local acidosis in tissue would normally counteract, but overall alkalosis + ↓iCa²⁺ tips the balance) ^[4]
Carpopedal spasm	Visible when severe — hands adopt "main d'accoucheur" posture ^[4]
Muscle fasciculations / Hyperreflexia	↓ionised Ca²⁺ → lower threshold for nerve depolarisation
Arrhythmias	Hypokalaemia (K⁺ shifts intracellularly in alkalosis) + ↓iCa²⁺ → prolonged QT, predisposition to atrial and ventricular arrhythmias
ECG changes	Hypokalaemia: ST depression, T wave flattening, U waves. Hypocalcaemia: prolonged QT interval ^[4]. Alkalosis itself can also prolong QT
Seizures (rare, in severe cases)	Profound cerebral vasoconstriction → cerebral ischaemia + ↓iCa²⁺ → lowered seizure threshold
Central neurological signs	If aetiology is CNS disease (stroke, tumour, etc.) — focal deficits may be present
Signs of underlying cause	Fever/rigors (sepsis), jaundice/spider naevi (liver failure), swollen calf (DVT/PE), anxiety features (psychogenic)

Understanding these shifts is crucial for interpreting lab results and predicting complications:

Potassium: Alkalosis → K⁺ shifts intracellularly → ↓ECF [K⁺] (hypokalaemia) ^[5]
- Mechanism: In alkalosis, H⁺ is scarce extracellularly. To maintain electroneutrality, K⁺ moves into cells as H⁺ moves out (H⁺/K⁺ exchange). Also, alkalosis stimulates Na⁺/K⁺-ATPase directly.
- Approximate shift: ~0.2–0.4 mEq/L drop in serum K⁺ per 0.1 unit rise in pH
- The hypokalaemia is a consequence (or parallel phenomenon) of alkalosis, not the cause ^[5]
Ionised Calcium: ↓ (as explained above — ↑albumin binding at higher pH) ^[4]
- Total calcium remains normal
- This is a functional/effective hypocalcaemia, not true calcium depletion
Phosphate: ↓ (alkalosis stimulates glycolysis by activating phosphofructokinase → phosphate is consumed in glycolysis and shifts intracellularly)
Chloride: May ↑ slightly (hyperchloraemia) as kidney retains Cl⁻ while excreting HCO₃⁻ during compensation

This deserves special mention as it is one of the most common presentations of acute respiratory alkalosis:

Definition: Recurrent episodes of hyperventilation, typically psychogenic, producing symptomatic respiratory alkalosis
Classic presentation: Young adult (often female) with acute anxiety → hyperventilation → paraesthesias (perioral, fingers, toes) → carpopedal spasm → lightheadedness → panic → further hyperventilation (vicious cycle)
Key features:
- Sighing respirations, air hunger
- Perioral and acral paraesthesias
- Carpopedal spasm (can be dramatic and frightening)
- Lightheadedness, sometimes syncope
- Chest tightness (can mimic cardiac chest pain)
- Often misdiagnosed as cardiac or neurological emergency

Clinical Pearl — Hyperventilation Syndrome vs Serious Pathology

Never assume hyperventilation is "just anxiety" without ruling out serious causes first! Young patients with PE, early asthma, pneumothorax, or diabetic ketoacidosis can all present with tachypnoea and anxiety. Always check:

SpO₂ (hypoxaemia points to organic cause)
ABG (a truly psychogenic hyperventilation should have normal pO₂ or supranormal pO₂ with low pCO₂)
ECG (rule out arrhythmia, PE signs)
Consider the clinical context (risk factors for PE, DKA, etc.)

The classic teaching of "breathing into a paper bag" to treat hyperventilation syndrome is no longer recommended in emergency settings because it could be dangerous if the patient actually has a pulmonary embolism or pneumothorax.

Organ System	Effect	Mechanism
CNS	Lightheadedness, confusion, syncope, seizures	Cerebral vasoconstriction (↓pCO₂ → ↓CBF, up to 35–40% reduction)
CVS	Tachycardia, arrhythmias, ↓cardiac output	Hypokalaemia, ↓iCa²⁺, direct effect of alkalosis on myocardium
Respiratory	Bronchoconstriction	Hypocapnia causes airway smooth muscle constriction
Neuromuscular	Paraesthesias, tetany, cramps	↓ionised Ca²⁺, ↓K⁺
Metabolic	Leftward shift of oxygen-haemoglobin dissociation curve	Alkalosis ↑ Hb's affinity for O₂ (Bohr effect) → ↓O₂ delivery to tissues
Renal	↑HCO₃⁻ excretion, ↓H⁺ excretion (compensation)	As described above

The leftward shift of the oxygen-haemoglobin dissociation curve in alkalosis means that even though PaO₂ may be normal, tissue O₂ delivery is impaired — Hb holds onto O₂ more tightly and releases it less readily at the tissue level. This is particularly important in critically ill patients.

Parameter	Acute	Chronic
pH	> 7.45 (↑)	Normal or slightly ↑ (7.38–7.42)
pCO₂	< 35 mmHg (↓) — primary change	< 35 mmHg (↓) — primary change
HCO₃⁻	Mildly ↓ (18–22 mEq/L)	Significantly ↓ (12–18 mEq/L)
Expected ΔHCO₃⁻	↓2 mEq/L per 10 mmHg ↓pCO₂	↓4–5 mEq/L per 10 mmHg ↓pCO₂
pO₂	Normal or ↓ (depends on cause)	Normal or ↓ (depends on cause)
Serum K⁺	↓ (mild shift)	May normalise
Ionised Ca²⁺	↓	May normalise if chronic

Compensation Formulas (Exam Essential)

For acute respiratory alkalosis:

Expected HCO₃⁻ = 24 − 2 × [(40 − measured pCO₂)/10]

For chronic respiratory alkalosis:

Expected HCO₃⁻ = 24 − 5 × [(40 − measured pCO₂)/10]

If the measured HCO₃⁻ is lower than expected → concurrent metabolic acidosis If the measured HCO₃⁻ is higher than expected → concurrent metabolic alkalosis

High Yield Summary

Respiratory alkalosis = hyperventilation → ↓pCO₂ → ↑pH — the most common acid-base disturbance in hospitalised patients
Chronic respiratory alkalosis is the ONLY acid-base disorder where compensation may be complete (normal pH) — because the kidney can effectively dump HCO₃⁻ over days
Key causes to remember: Anxiety/hyperventilation syndrome, pneumonia, PE, sepsis (often earliest sign!), liver failure (HBV cirrhosis — very HK-relevant), salicylate poisoning, pregnancy, mechanical over-ventilation
Salicylate poisoning = mixed respiratory alkalosis + metabolic acidosis (unique combination)
Symptoms arise from: ↓ionised Ca²⁺ (paraesthesias, tetany, Chvostek/Trousseau signs), cerebral vasoconstriction (dizziness, syncope, confusion), and ↓K⁺ (arrhythmias)
Compensation formulas: Acute ΔHCO₃⁻ = 2 per 10 mmHg ΔpCO₂; Chronic ΔHCO₃⁻ = 4–5 per 10 mmHg ΔpCO₂
Never dismiss tachypnoea as "just anxiety" — always rule out PE, pneumothorax, DKA, and other serious causes
Alkalosis shifts K⁺ intracellularly and ↑Hb-O₂ affinity (leftward Bohr shift) → impairs tissue O₂ delivery

Active Recall - Respiratory Alkalosis (Definition through Clinical Features)

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.310, Section 9.1 Acid-base Disorders) ^[2] Senior notes: Ryan Ho Urogenital.pdf (p.34, Section 2.4.1 Approach to Acid-base Disorders); Block A - Electrolyte and Acid-Base Disorders.pdf (p.2-3) ^[3] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf; MBBS IV Electrolytes_2024.pdf; Block A - Electrolyte and Acid-Base Disorders.pdf ^[4] Senior notes: Ryan Ho Endocrine.pdf (p.45, Section 2.3 Hypocalcemia) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p.13, Potassium homeostasis — transcellular shift in alkalosis) ^[6] Senior notes: Ryan Ho Psychiatry.pdf (p.180, Panic disorder — cognitive theory)

Differential Diagnosis of Respiratory Alkalosis

When you encounter a patient with low pCO₂ and elevated (or near-normal) pH, the clinical task is twofold:

Confirm that the respiratory alkalosis is the primary disorder (and not compensatory hyperventilation for a metabolic acidosis)
Identify the underlying cause driving the hyperventilation

These are two distinct questions, and confusing them is one of the most common exam mistakes.

This is the critical first-principles question that must be answered before constructing any differential.

Compensatory respiratory alkalosis = hyperventilation to expel CO₂, reduced pCO₂ occurs in response to a primary metabolic acidosis (loss of HCO₃⁻) ^[1]. In this situation, the low pCO₂ is appropriate — it is the body's attempt to restore pH. The clinical features will be those of the metabolic acidosis (e.g., DKA, lactic acidosis, renal failure) rather than a primary respiratory problem.

How to distinguish:

Feature	Primary Respiratory Alkalosis	Compensatory Respiratory Alkalosis (for metabolic acidosis)
pH	> 7.45 (acute) or normal (chronic, fully compensated)	< 7.35 (pH still acidotic because metabolic acidosis is the primary driver)
Primary change	↓pCO₂ is the initiating event	↓HCO₃⁻ is the initiating event; ↓pCO₂ follows
Direction of pH	Alkalotic (or normal if chronic)	Acidotic
HCO₃⁻	Secondarily low (compensation)	Primarily low (the original problem)
Clinical context	Anxiety, PE, sepsis, liver disease, etc.	DKA, lactic acidosis, renal failure, diarrhoea, etc.
Characteristic sign	—	Kussmaul's breathing → hyperventilation in an attempt to expel as much pCO₂ as possible ^[1]

Three-step approach when interpreting ABG: (1) Look at pH — direction of change often indicates primary/predominant disorder. (2) Pattern recognition — "3 ups/3 downs rule": if ALL 3 components of H-H equation (pH, HCO₃⁻, pCO₂) move in same direction, there must be a simple metabolic disturbance. "Not up, not down rule": if HCO₃⁻ and CO₂ move in different directions, there must be mixed acid-base disturbance. (3) Evaluate compensation to uncover subtle mixed disorders. ^[2]

Exam Trap — Don't Confuse Compensation with Primary Disorder

A patient with DKA will have low HCO₃⁻ AND low pCO₂. The low pCO₂ is compensatory (secondary hyperventilation), NOT primary respiratory alkalosis. The pH will be acidotic. Do not list respiratory alkalosis as part of the differential for a DKA patient's ABG — it is compensation.

Conversely, a patient with salicylate poisoning has a TRUE mixed disorder: primary respiratory alkalosis (direct medullary stimulation) PLUS primary metabolic acidosis (organic acid accumulation) ^[3]^[2]. Here the actual pCO₂ is lower than expected for pure compensation of the metabolic acidosis — this is how you unmask the mixed picture.

Once you've confirmed ↓pCO₂ with ↑pH (or normal pH if chronic) and the compensation fits:

Acute: Expected ↓[HCO₃⁻] = 2 mmol/L per 10 mmHg (1.3 kPa) drop in pCO₂; [HCO₃⁻] cannot go lower than ~18 mmol/L ^[2]
Chronic: Expected ↓[HCO₃⁻] = 4 mmol/L per 10 mmHg (1.3 kPa) drop in pCO₂; [HCO₃⁻] cannot go lower than ~12 mmol/L (can fully compensate) ^[2]

If measured HCO₃⁻ is lower than expected → concurrent primary metabolic acidosis exists (mixed disorder) If measured HCO₃⁻ is higher than expected → concurrent primary metabolic alkalosis exists (mixed disorder)

Now the real clinical question: Why is this patient hyperventilating?

The differential is best structured by mechanism of hyperventilation, which maps directly to the pathophysiology:

Detailed Differential Diagnosis Table

These are causes where the hyperventilation is a physiological response to hypoxaemia — the body is trying to improve oxygenation, and in the process blows off CO₂.

Cause	Key Differentiating Features	Why It Causes Resp Alkalosis
Pneumonia	Fever, productive cough, crackles, consolidation on CXR, raised WBC/CRP	V/Q mismatch + shunt → hypoxaemia → ↑ventilatory drive; also systemic inflammatory mediators stimulate respiratory centre
Pulmonary embolism	Pleuritic chest pain, swollen calf (DVT), risk factors (immobility, OCP, malignancy). ABG: hypoxaemia, hypocapnia, respiratory alkalosis, ↑A-a gradient ^[4]	Dead space ventilation ↑ (clot blocks perfusion to ventilated areas) → V/Q mismatch → hypoxaemia; also J-receptor stimulation. Type I respiratory failure ^[4]
Acute asthma (early/moderate)	Wheeze, ↓PEFR, history of asthma. NOTE: pCO₂ rising toward normal in acute asthma is DANGER SIGN (exhaustion)	Airway obstruction with preserved respiratory drive → hyperventilation of non-obstructed areas → ↓pCO₂. Late severe attack → fatigue → T2RF
Interstitial lung disease	Exertional dyspnoea, fine inspiratory crackles, clubbing, restrictive PFTs	Diffusion impairment → hypoxaemia on exertion → ↑drive; also ↓compliance stimulates stretch receptors
ARDS	Acute bilateral infiltrates, severe hypoxaemia, known precipitant (sepsis, trauma, aspiration)	Diffuse alveolar damage → shunt + ↓compliance → ↑respiratory drive
High altitude	Travel history (> 2500 m)	↓Atmospheric pO₂ → hypoxaemia → carotid body stimulation → hyperventilation
Severe anaemia	Pallor, fatigue, tachycardia, low Hb	↓O₂ carrying capacity → tissue hypoxia → ↑ventilatory drive (even though pO₂ may be normal, CaO₂ is low)
Cyanotic congenital heart disease / R-to-L shunt	Cyanosis from birth, clubbing, characteristic murmurs	Deoxygenated blood bypasses lungs → systemic hypoxaemia

High Yield — Pulmonary Embolism ABG Pattern

PE classically presents with Type I respiratory failure: hypoxaemia + hypocapnia + respiratory alkalosis + elevated A-a gradient ^[4]^[5]. The A-a gradient is elevated because there is true V/Q mismatch (perfusion lost to embolised segments while ventilation continues). This is a favourite exam ABG question. A normal A-a gradient in the setting of respiratory alkalosis argues AGAINST PE and towards psychogenic hyperventilation.

These are potentially dangerous causes where the respiratory centre is driven despite adequate oxygenation.

Cause	Key Differentiating Features	Why It Causes Resp Alkalosis
Sepsis / SIRS	Fever/hypothermia, tachycardia, hypotension, raised WBC/CRP/procalcitonin, source of infection	Endotoxins (especially gram-negative) and pro-inflammatory cytokines (TNF-α, IL-1, IL-6) directly stimulate medullary respiratory centre. Respiratory alkalosis may be the earliest laboratory abnormality in sepsis — before fever, before hypotension
Hepatic failure / Cirrhosis	Jaundice, spider naevi, palmar erythema, ascites, encephalopathy, coagulopathy. Very relevant in HK (HBV)	Circulating toxins (ammonia, progesterone, endogenous benzodiazepine-like substances) stimulate respiratory centre; portosystemic shunting allows toxins to bypass liver. Chronic respiratory alkalosis is a characteristic finding in stable cirrhosis
CNS pathology	Focal neurological signs, altered consciousness, neck stiffness (meningitis), history of trauma	Direct irritation/damage to brainstem respiratory centres: stroke, tumour, meningitis/encephalitis, subarachnoid haemorrhage, TBI. Central neurogenic hyperventilation (rare but classic) = sustained rapid deep breathing from brainstem lesions
Salicylate poisoning	Mixed respiratory alkalosis + metabolic acidosis. ABG: resp alkalosis early on → becomes dominated by HAGMA in late stages ^[3]. Tinnitus, vertigo, nausea/vomiting, hyperpnoea early; altered mental status, hyperpyrexia later. Suspect salicylate poisoning in acid-base disorder of unknown origin ^[3]	Direct stimulation of medulla → ↑rate and depth of respiration ^[3]. Simultaneously causes HAGMA from ketoacidosis, lactic acidosis and salicylate accumulation
Progesterone	Pregnancy (physiological), medroxyprogesterone use	Progesterone directly stimulates central chemoreceptors → ↓pCO₂ set point. Normal pregnancy: pCO₂ ~28–32 mmHg. Not pathological in pregnancy but may confuse interpretation
Methylxanthines	Theophylline toxicity — nausea, vomiting, tremor, seizures; caffeine excess	Direct stimulation of respiratory centre
Thyrotoxicosis	Weight loss, tremor, tachycardia, AF, goitre, exophthalmos	↑Metabolic rate → ↑CO₂ production + direct central stimulation → net ↓pCO₂
Heart failure	Exertional dyspnoea, orthopnoea, PND, oedema, raised JVP, S3 gallop	Pulmonary congestion → J-receptor stimulation → reflex tachypnoea; also mild hypoxaemia from pulmonary oedema (shunt)

High Yield — Liver Failure and Respiratory Alkalosis in HK Context

Given HK's high HBV carrier rate (~7–8%), chronic liver disease and cirrhosis are common. Chronic respiratory alkalosis is a hallmark finding in stable cirrhosis — the ABG may show a fully compensated picture (normal pH, low pCO₂, low HCO₃⁻). When these patients decompensate (sepsis, GI bleeding, hepatorenal syndrome), additional acid-base disorders stack on top of the chronic respiratory alkalosis, creating complex mixed pictures. Always establish the patient's baseline ABG when interpreting.

Cause	Key Differentiating Features	Why It Causes Resp Alkalosis
Anxiety / Panic disorder	Young adult, episodic attacks, sense of doom, palpitations, trembling. DSM-5: recurrent unexpected panic attacks with ≥ 4 symptoms (palpitations, sweating, trembling, SOB, choking, chest pain, nausea, dizziness, chills, paraesthesias, derealization, fear of losing control, fear of dying) + ≥ 1 month of persistent concern/maladaptive behaviour ^[6]. Hyperventilation as a somatic feature — dizziness, paraesthesia of extremities, paradoxical feeling of SOB ^[7]	Cortical/limbic override of brainstem ventilatory control → voluntary/involuntary hyperventilation. Cognitive theory: anxiety → physical symptoms → ↑anxiety (downward spiral) ^[7]
Hyperventilation syndrome	Recurrent episodes, often female, classic perioral/acral paraesthesias + carpopedal spasm, normal pO₂ and normal A-a gradient on ABG	Same as anxiety-driven; may become habitual pattern
Pain	Acute injury, post-operative, procedural	Cortical and limbic pain pathways drive hyperventilation

Critical Point — Psychogenic Hyperventilation is a Diagnosis of EXCLUSION

Never diagnose "hyperventilation syndrome" or "anxiety" as the cause of respiratory alkalosis without first ruling out organic causes. Key red flags that MUST prompt further workup:

Hypoxaemia (pO₂ < 80 mmHg or SpO₂ < 95%) → cannot be psychogenic
Elevated A-a gradient → suggests V/Q mismatch, shunt, or diffusion impairment (organic)
Fever → sepsis, pneumonia
Unilateral leg swelling → DVT/PE
Focal neurological signs → CNS pathology
Metabolic acidosis component → salicylate poisoning, DKA, sepsis-related lactic acidosis

A truly psychogenic cause should show: normal pO₂ (often supranormal — > 100 mmHg), normal A-a gradient, low pCO₂, elevated pH, no other abnormalities.

Cause	Key Differentiating Features	Mechanism
Mechanical over-ventilation	ICU patient on ventilator, ABG shows unexpectedly low pCO₂	Excessive tidal volume or respiratory rate set too high → alveolar ventilation exceeds CO₂ production → ↓pCO₂

These are scenarios where respiratory alkalosis is one component of a complex picture:

Mixed Disorder	Classic Example	How to Recognise
Respiratory alkalosis + Metabolic acidosis	Salicylate poisoning ^[3]^[2]	Actual pCO₂ < expected pCO₂ for the degree of metabolic acidosis ^[2]. pH may be near-normal (the two disorders have opposing effects on pH). Elevated anion gap clinches metabolic acidosis
Respiratory alkalosis + Metabolic acidosis	Sepsis (lactic acidosis + direct respiratory stimulation)	Similar to above; lactic acid elevates AG, and pCO₂ is lower than expected for compensation alone
Respiratory alkalosis + Metabolic alkalosis	Hepatic failure (chronic resp alk) + vomiting (met alk)	HCO₃⁻ higher than expected for chronic compensation; pH markedly elevated
Chronic respiratory alkalosis + Acute metabolic acidosis	Cirrhotic patient with new GI bleed → lactic acidosis	Baseline chronic resp alk (low pCO₂, low HCO₃⁻, normal pH) then acute metabolic acidosis drops pH

"Not up, not down rule": if HCO₃⁻ and CO₂ move in different directions, there must be a mixed acid-base disturbance ^[2]. In respiratory alkalosis, both pCO₂ and HCO₃⁻ move downward (same direction) — this is a "simple" disorder. If HCO₃⁻ is paradoxically normal or elevated while pCO₂ is low, suspect a concurrent metabolic alkalosis.

In paediatrics, unexplained respiratory alkalosis should raise suspicion for inborn errors of metabolism ^[8]:

Alarming features: significant metabolic acidosis, unexplained respiratory alkalosis, hypoketotic hypoglycaemia ^[8]
Urea cycle defects: hyperammonaemia directly stimulates the respiratory centre → respiratory alkalosis + encephalopathy
- Why: ammonia is a potent central respiratory stimulant; the combination of respiratory alkalosis + high ammonia + encephalopathy in a neonate/infant is classic for urea cycle enzyme defects
Organic acidaemias: may present with mixed picture (metabolic acidosis from organic acids + respiratory alkalosis from central stimulation)
Clinical features resemble intoxication but without history of ingestion/exposure; or resemble infection but no organism isolated ^[8] → think IEM

Category	Causes	Key Distinguishing Clue
Hypoxia-driven	Pneumonia, PE, asthma, ILD, ARDS, altitude, anaemia, R→L shunt	↓pO₂, ↑A-a gradient
Sepsis / SIRS	Gram-negative sepsis, any severe infection	Fever, ↑WBC, ↑procalcitonin; resp alk may be earliest sign
Hepatic	Cirrhosis (HBV, HCV, alcoholic), acute liver failure	Jaundice, coagulopathy, encephalopathy; chronic resp alk
CNS	Stroke, tumour, meningitis, encephalitis, TBI, SAH	Focal neurology, altered GCS, neck stiffness
Drug / Toxin	Salicylates, theophylline, caffeine, progesterone	Drug history; salicylate = mixed resp alk + met acidosis
Endocrine	Thyrotoxicosis, pregnancy	Thyroid signs or positive pregnancy test
Cardiac	Heart failure	Orthopnoea, oedema, raised JVP
Iatrogenic	Mechanical over-ventilation	ICU setting, ventilator parameters
Psychogenic	Anxiety, panic disorder, hyperventilation syndrome, pain	Diagnosis of exclusion; normal pO₂, normal A-a gradient
Metabolic (paediatric)	Urea cycle defects, organic acidaemias	Neonatal/infant encephalopathy, hyperammonaemia, consanguinity

The alveolar-arterial (A-a) gradient is a powerful tool for separating causes:

A-a Gradient	Interpretation	Causes of Resp Alkalosis
Normal (< 15 mmHg, age-adjusted: 2.5 + 0.21 × age)	The lungs themselves are fine; hyperventilation is from a non-pulmonary driver	Psychogenic (anxiety, pain), CNS (stroke, tumour), Drugs (salicylates, progesterone), Hepatic, Pregnancy, Mechanical over-ventilation
Elevated	There is a genuine pulmonary gas exchange problem	Pneumonia (shunt), PE (V/Q mismatch), ILD (diffusion impairment), ARDS, Heart failure (pulmonary oedema)

In PE: ABG shows hypoxaemia, hypocapnia, respiratory alkalosis, and ↑A-a gradient ^[4]. A normal A-a gradient effectively rules against PE as a cause.

When you see a patient with confirmed primary respiratory alkalosis:

Check pO₂ and A-a gradient → Is this hypoxia-driven?
- If yes → chest pathology or systemic hypoxia (PE, pneumonia, ILD, anaemia, etc.)
- If no → move to step 2
Look for signs of serious organic disease:
- Fever / sepsis markers → sepsis (most dangerous — resp alk may be the only early clue)
- Liver stigmata → hepatic failure (very common in HK)
- Focal neurology / altered GCS → CNS pathology
- Drug history → salicylates (check serum level if any doubt), theophylline
Consider endocrine / physiological:
- Pregnancy test in women of reproductive age
- Thyroid function tests if thyrotoxicosis suspected
ICU patient? → Check ventilator settings → mechanical over-ventilation
Only when ALL organic causes excluded → consider psychogenic / hyperventilation syndrome

High Yield Summary — Differential Diagnosis of Respiratory Alkalosis

First step: confirm it's primary respiratory alkalosis, not compensatory hyperventilation for metabolic acidosis (look at pH direction)
Use A-a gradient: elevated → pulmonary pathology (PE, pneumonia, ILD); normal → non-pulmonary (psychogenic, CNS, liver, drugs)
Top dangerous causes to never miss: PE, sepsis (earliest sign!), salicylate poisoning, CNS pathology
Salicylate poisoning = mixed respiratory alkalosis + HAGMA — suspect in any acid-base disorder of unknown origin ^[3]
PE ABG: hypoxaemia + hypocapnia + respiratory alkalosis + ↑A-a gradient + Type I respiratory failure ^[4]
Liver failure (HBV cirrhosis in HK) → chronic respiratory alkalosis, often fully compensated
Psychogenic is a diagnosis of EXCLUSION — must have normal pO₂ and normal A-a gradient
In paediatrics: unexplained respiratory alkalosis + encephalopathy → think urea cycle defects (hyperammonaemia) ^[8]
Mixed disorders: use compensation formulae and "not up, not down" rule to unmask ^[2]

Active Recall - Differential Diagnosis of Respiratory Alkalosis

References

^[1] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p.3, Compensatory mechanisms) ^[2] Senior notes: Ryan Ho Urogenital.pdf (p.35, Expected compensation table and three-step ABG approach) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (p.42, Section E Salicylate); Ryan Ho Urogenital.pdf (p.48, Aspirin toxicity) ^[4] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p.967, ABG findings in PE) ^[5] Senior notes: Ryan Ho Respiratory.pdf (p.29, Type 1 respiratory failure causes — PE) ^[6] Senior notes: Ryan Ho Psychiatry.pdf (p.179, DSM-5 diagnostic criteria for panic disorder) ^[7] Senior notes: Ryan Ho Psychiatry.pdf (p.173, GAD somatic features — hyperventilation) ^[8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.463, Inborn errors of metabolism — alarming features including unexplained respiratory alkalosis)

Diagnostic Criteria for Respiratory Alkalosis

Respiratory alkalosis is not a "disease" with formal diagnostic criteria like lupus or rheumatic fever — it is a laboratory diagnosis made on arterial blood gas (ABG) analysis. However, there is a rigorous, stepwise approach to confirming it, classifying its chronicity, detecting mixed disorders, and identifying the underlying cause. This is effectively the "diagnostic criteria."

Respiratory alkalosis is defined by: ^[2]

↓pCO₂ < 35 mmHg (< 4.7 kPa) — the primary derangement (hyperventilation blowing off CO₂)
pH > 7.45 (acute) or pH normal 7.35–7.45 (chronic, fully compensated)
↓[HCO₃⁻] — secondary/compensatory (kidney excreting bicarbonate)

Key Diagnostic Principle

The Henderson-Hasselbalch equation defines the acid-base behaviour in the body: change in pH follows direction of change of HCO₃⁻:CO₂ ratio ^[2]. In respiratory alkalosis, CO₂ drops (denominator falls) → ratio rises → pH rises. The low HCO₃⁻ is always secondary compensation — never the primary change.

This distinction is clinically crucial because it determines (a) whether the compensation is appropriate and (b) whether a mixed disorder is hiding underneath.

Criterion	Acute Respiratory Alkalosis	Chronic Respiratory Alkalosis
Duration	< 24–48 hours	> 2–5 days
pH	Elevated (> 7.45)	Normal or near-normal ^[2]^[9]
pCO₂	< 35 mmHg	< 35 mmHg
Expected compensation	↓[HCO₃⁻] = 2 mmol/L per 10 mmHg (1.3 kPa) drop in pCO₂; minimum ~18 mmol/L ^[2]	↓[HCO₃⁻] = 4 mmol/L per 10 mmHg (1.3 kPa) drop in pCO₂; minimum ~12 mmol/L ^[2]
Mechanism of compensation	Intracellular buffering only (H⁺ released from proteins, Hb, phosphate)	Renal: ↓proximal HCO₃⁻ reabsorption + ↓distal H⁺ secretion

Remarks: "1-2-3-4" rule for compensation of acute and chronic respiratory acidosis and alkalosis: Acute resp acidosis = 1, acute resp alkalosis = 2, chronic resp acidosis = 3, chronic resp alkalosis = 4 (mmol/L change in HCO₃⁻ per 10 mmHg change in pCO₂) ^[10]

Rule of thumb: ONLY in chronic respiratory alkalosis there may be complete compensation (i.e. normal pH) ^[2]^[9]

Once you've confirmed respiratory alkalosis, you must check whether compensation is appropriate. If not, a concurrent metabolic disorder is present:

Finding	Interpretation
Measured HCO₃⁻ matches expected	Simple (pure) respiratory alkalosis
Measured HCO₃⁻ lower than expected	Concurrent primary metabolic acidosis (e.g., salicylate poisoning, sepsis with lactic acidosis) ^[2]
Measured HCO₃⁻ higher than expected	Concurrent primary metabolic alkalosis (e.g., cirrhotic patient with vomiting) ^[2]

Three-step approach when interpreting ABG: ^[2]

Look at pH: direction of change often indicates primary/predominant acidosis/alkalosis

Pattern recognition: "3 ups/3 downs rule" — if ALL 3 components (pH, HCO₃⁻, pCO₂) move in same direction, there must be a simple metabolic disturbance. "Not up, not down rule" — if HCO₃⁻ and CO₂ move in different directions, there must be mixed acid-base disturbance

Evaluate compensation to uncover subtle mixed disorders

Applying the 3-Step Approach to Respiratory Alkalosis

In pure respiratory alkalosis, pH goes up, pCO₂ goes down, and HCO₃⁻ goes down → pH moves opposite to the other two → this is a simple respiratory disturbance (not metabolic, because in simple metabolic disorders all three move in the same direction). If you see pH up, pCO₂ down, but HCO₃⁻ up or normal → HCO₃⁻ and CO₂ are moving in different directions → mixed acid-base disturbance ^[2].

Case: F/75, drug overdose. ABG: pH 7.54 (H), pCO₂ 2.83 kPa (L), pO₂ 23.76 kPa (H), HCO₃⁻ 15.7 mmol/L (L), BE -4.8 (L). Salicylate 4.42 mmol/L (> 2.2). ^[3]

Step-by-step interpretation:

pH 7.54 → alkalaemic → predominant process is alkalosis
pCO₂ 2.83 kPa (≈21 mmHg) → very low → primary respiratory alkalosis present
Check compensation: ΔpCO₂ = 40 - 21 = 19 mmHg. For acute resp alk: expected ΔHCO₃⁻ = 2 × (19/10) = 3.8; expected HCO₃⁻ = 24 - 3.8 ≈ 20.2 mmol/L
Measured HCO₃⁻ = 15.7 → much lower than expected 20.2 → concurrent metabolic acidosis ^[3]
This confirms a mixed respiratory alkalosis + metabolic acidosis → classic salicylate poisoning pattern ^[3]^[2]
Anion gap: Na 138 - Cl (not given but can be estimated) — the elevated AG confirms unmeasured anions (salicylate, lactate, ketoacids)

"In acute respiratory alkalosis, immediate bicarbonate buffer compensation can only result in 2 mmol/L drop in HCO₃⁻ per each 1.33 kPa drop in pCO₂. In this case, the expected HCO₃⁻ is at ~20 mmol/L; we can thus conclude an underlying metabolic acidosis is present. This can be verified by anion gap (↑AG → anion present). Note that base excess does not give extra info over [HCO₃⁻]." ^[3]

The following algorithm integrates ABG interpretation, chronicity assessment, mixed disorder detection, and aetiological workup:

Investigation Modalities — Systematic Approach

The investigations for respiratory alkalosis serve two purposes:

Confirm and characterise the acid-base disorder (ABG, electrolytes)
Identify the underlying aetiology (targeted tests based on clinical suspicion)

A. Confirming the Acid-Base Disorder

ABG is the definitive investigation for diagnosing respiratory alkalosis ^[7]^[11].

Parameter	Normal Range	Finding in Resp Alkalosis	Interpretation
pH	7.35–7.45	> 7.45 (acute) or normal (chronic)	Confirms alkalaemia or compensated alkalosis
pCO₂	35–45 mmHg (4.7–6.0 kPa)	< 35 mmHg (< 4.7 kPa)	Primary derangement — hyperventilation
pO₂	75–100 mmHg (10–13 kPa)	Variable (↓ if hypoxia-driven, normal/↑ if psychogenic)	Distinguishes pulmonary vs non-pulmonary causes
HCO₃⁻	22–26 mmol/L	↓ (18–22 acute; 12–18 chronic)	Compensatory renal excretion
Base excess	-2 to +2	Negative (more so in chronic)	Base excess does not give extra info over [HCO₃⁻] ^[3]

Interpret ABG using a stepwise approach: assess oxygenation via PaO₂ and A-a gradient, determine acid-base status through pH, identify primary disorder from PaCO₂ and bicarbonate, then calculate compensation ^[7]

A-a gradient calculation:

$P_AO_2 = FiO_2 \times (P_{atm} - P_{H_2O}) - \frac{PaCO_2}{R}$

Or simplified: PAO₂ (in kPa) = FiO₂ × 94.5 − PaCO₂ × 1.25 ^[11]

Normal A-a gradient: < 15 mmHg (age-adjusted: 2.5 + 0.21 × age), or < 2.7 kPa ^[11]
↑A-a gradient (> 2.7 kPa): due to V/Q mismatch, diffusion abnormalities ^[11]

A-a Gradient	Significance for Resp Alkalosis
Normal	Lungs are fine; hyperventilation driven by non-pulmonary cause (anxiety, CNS, liver, drugs, pregnancy)
Elevated	Pulmonary gas exchange problem → PE, pneumonia, ILD, ARDS, pulmonary oedema

High Yield — Venous vs Arterial Blood Gas

Note the source of blood sample determines interpretation: ^[2]

Arterial BG: pH 7.36–7.44, [HCO₃⁻] 21–27 mmol/L, pCO₂ 36–44 mmHg (4.8–5.9 kPa)
Peripheral venous BG: usually add 0.02–0.04 to pH, subtract 1–2 mmol/L from [HCO₃⁻] and 3–8 mmHg from pCO₂
Central venous BG: usually add 0.03–0.05 to pH and 4–5 mmHg from pCO₂

In practice, a venous blood gas (VBG) can screen for acid-base status (pH and HCO₃⁻ are reasonably accurate), but pO₂ on VBG is meaningless — you cannot assess oxygenation or calculate A-a gradient from a VBG. If you need oxygenation data, you must get an ABG.

Test	Expected Finding	Why
K⁺	↓ (hypokalaemia)	Alkalosis drives K⁺ intracellularly (H⁺/K⁺ exchange)
Ionised Ca²⁺	↓	↑pH → ↑albumin-Ca²⁺ binding → ↓free Ca²⁺
Phosphate	↓	Respiratory alkalosis results in ↓cellular CO₂. The resultant high cellular pH stimulates Krebs cycle, resulting in consumption of phosphate ^[12] — also glycolysis consumes phosphate
Na⁺	Usually normal	May be deranged depending on underlying cause
Cl⁻	May be ↑ (hyperchloraemia)	Kidney retains Cl⁻ as it excretes HCO₃⁻ in compensation

Hypokalemia is usually associated with alkalosis ^[13]. Always check serum bicarbonate alongside potassium — if hypoK and metabolic acidosis → indicates renal tubular acidosis; if hypoK and alkalosis → more commonly vomiting, diuretics, or secondary to the alkalosis itself ^[13]^[14]

Anion gap = Na⁺ − Cl⁻ − HCO₃⁻ ^[1]
Normal anion gap = 8–14 ^[1]
Why calculate it? To detect a concurrent high anion gap metabolic acidosis (HAGMA) hidden behind the respiratory alkalosis
- If AG > 14 in a patient with respiratory alkalosis → there is a concurrent metabolic acidosis with unmeasured anions (e.g., salicylate poisoning: resp alkalosis early → becomes dominated by HAGMA in late stages ^[3])

Low bicarbonate does not mean metabolic acidosis — could be the compensatory mechanism to a primary respiratory alkalosis (e.g., something causing hyperventilation) ^[1]. Conversely, if HCO₃⁻ is low AND the AG is elevated, the low HCO₃⁻ is not just compensation — there is a true metabolic acidosis as well.

B. Identifying the Underlying Aetiology

Once respiratory alkalosis is confirmed, targeted investigations depend on clinical suspicion:

Quick bedside screen for hypoxaemia
SpO₂ < 94% in a hyperventilating patient → likely hypoxia-driven cause → proceed to CXR, CTPA, etc.
SpO₂ normal → non-pulmonary cause more likely

Finding	Suggests
Consolidation / air bronchograms	Pneumonia
Bilateral alveolar infiltrates	ARDS ^[15]
Pleural effusion, blunted costophrenic angle	PE (also pneumonia, HF)
Peripheral wedge-shaped opacity (Hampton hump)	PE ^[16]
Focal oligaemia (Westermark sign)	PE ^[16]
Pulmonary oedema (upper lobe venous diversion, Kerley B lines)	Heart failure
Reticular/honeycombing pattern	ILD
Normal CXR	Anxiety, PE (CXR normal in 12–22% of PE ^[16]), early sepsis, drugs, liver disease

Finding	Suggests
Sinus tachycardia	Non-specific (anxiety, PE, sepsis, thyrotoxicosis)
S1Q3T3 pattern	PE (massive) ^[16]
RV strain: T wave inversion V1–V4, new RBBB, RAD, P pulmonale	PE (massive) ^[16]
ST depression, flat T, U waves	Hypokalaemia (consequence of alkalosis)
Prolonged QTc	Hypocalcaemia (↓ionised Ca²⁺ from alkalosis)
AF	PE, thyrotoxicosis

Investigation	What It Tells You	When to Order
CBC with differentials	↑WBC (sepsis, pneumonia), ↓Hb (severe anaemia as cause), ↑eosinophil (anaphylaxis)	Routine
CRP / Procalcitonin	Infection/sepsis markers	Fever, suspected sepsis
LFT	Deranged LFT → liver failure/cirrhosis causing chronic resp alkalosis	Jaundice, liver stigmata, known HBV
Ammonia (NH₃)	↑↑ in urea cycle defects (paediatric) and hepatic encephalopathy; NH₃ is a potent ventilatory stimulator → respiratory alkalosis ^[8]	Encephalopathy, neonatal/infant, liver failure
RFT	AKI (sepsis-related), CKD (as underlying cause of acidosis in mixed disorder)	Routine
Lactate	↑ in sepsis, shock (lactic acidosis component of mixed disorder)	Suspected sepsis or shock
Serum salicylate level	Therapeutic 10–30 mg/dL; toxic > 40 mg/dL ^[3]. Suspect salicylate poisoning in acid-base disorder of unknown origin ^[3]	Any unexplained mixed resp alk + met acidosis, drug OD
Urine toxicology screen	Identifies salicylates, methylxanthines, other drugs	Suspected poisoning
D-dimer	Sensitive (↑↑NPV) but not specific; only used to rule out venous thrombosis if absent ^[16]	Suspected PE (low-risk Wells score)
Thyroid function tests	Thyrotoxicosis	Goitre, tremor, AF, weight loss
β-hCG	Pregnancy	Women of reproductive age with unexplained chronic resp alk
Blood cultures	Identify causative organism in sepsis	Fever, suspected sepsis

Investigation	Indication	Key Findings
CTPA (CT Pulmonary Angiography)	Suspected PE	Intraluminal filling defects in pulmonary arteries
CT Brain	Suspected CNS pathology (stroke, tumour, SAH)	Infarct, haemorrhage, mass, meningeal enhancement
HRCT Thorax	Suspected ILD	Ground-glass opacities, honeycombing, traction bronchiectasis
Echocardiography	Suspected heart failure or PE (RV strain)	RV dilatation/dysfunction, McConnell's sign (regional RV wall motion abnormality) in PE; EF assessment in HF
Lumbar puncture	Suspected meningitis/encephalitis	CSF analysis: cells, protein, glucose, culture, PCR

When unexplained respiratory alkalosis is found in a neonate or infant with encephalopathy ^[8]:

Investigation	Finding	Diagnosis
Plasma ammonia (NH₃)	↑↑ (> 100 μmol/L in term neonates)	Urea cycle defects ^[8]
ABG pattern	↑pH, ↓pCO₂, ↓HCO₃⁻ (respiratory alkalosis with 2° metabolic compensation) — because NH₃ is a potent ventilatory stimulator	Urea cycle enzyme defects ^[8]
Plasma amino acids	↑glutamine, ↑citrulline (distal defects) or ↓citrulline (proximal defects)	Specific urea cycle defect
Urine organic acids	Pattern of organic acid accumulation	Organic acidaemias
Acylcarnitine profile	Specific patterns	Fatty acid oxidation defects, organic acidaemias

Contrast with organic acidaemias which give ↓pH, ↓pCO₂, ↓HCO₃⁻ (metabolic acidosis with 2° hyperventilation) ^[8]

Phase	Investigation	Purpose
1. Confirm disorder	ABG (gold standard)	pH, pCO₂, pO₂, HCO₃⁻, A-a gradient
1. Confirm disorder	Serum electrolytes (K⁺, Ca²⁺, PO₄³⁻, Na⁺, Cl⁻)	Detect consequences + calculate AG
2. Assess severity	Pulse oximetry	Rapid hypoxaemia screen
2. Assess severity	ECG	Arrhythmias from ↓K⁺/↓iCa²⁺; PE signs
3. Identify cause	CXR	Pneumonia, PE signs, ARDS, ILD, HF
3. Identify cause	CBC, CRP, blood cultures, lactate	Sepsis workup
3. Identify cause	LFT, NH₃	Liver failure / cirrhosis
3. Identify cause	Salicylate level, urine tox screen	Drug poisoning
3. Identify cause	D-dimer, CTPA	PE
3. Identify cause	TFTs, β-hCG	Thyrotoxicosis, pregnancy
3. Identify cause	CT brain, LP	CNS causes
3. Identify cause (paeds)	NH₃, amino acids, organic acids, acylcarnitine	Inborn errors of metabolism

Normal pH value with ↓HCO₃⁻ and ↓pCO₂ → Metabolic acidosis + Respiratory alkalosis ^[10]

This is a crucial interpretation. When you see:

pH normal (~7.40)
HCO₃⁻ low
pCO₂ low

It could be either:

Chronic compensated respiratory alkalosis (the kidney has had time to dump HCO₃⁻, restoring pH) — only in chronic respiratory alkalosis may there be complete compensation ^[2]^[9]
Mixed metabolic acidosis + respiratory alkalosis (the two processes cancel each other's pH effects) — check anion gap: if AG elevated → there IS a metabolic acidosis present ^[10]

The clinical context and anion gap distinguish them:

Stable cirrhotic, no acute illness, normal AG → chronic compensated respiratory alkalosis
Septic patient, elevated lactate, elevated AG → mixed disorder

High Yield Summary — Diagnosis of Respiratory Alkalosis

ABG is the gold standard: ↓pCO₂ + ↑pH (acute) or normal pH (chronic) + ↓HCO₃⁻
Use the "1-2-3-4 rule": acute resp alk compensation = 2 mmol/L ↓HCO₃⁻ per 10 mmHg ↓pCO₂; chronic = 4 mmol/L ^[2]^[10]
Always check if compensation is appropriate — if HCO₃⁻ lower than expected → mixed with met acidosis; if higher → mixed with met alkalosis ^[2]
A-a gradient separates pulmonary (↑) from non-pulmonary (normal) causes
Calculate anion gap to unmask hidden HAGMA (especially salicylate poisoning) ^[1]^[3]
Salicylate level should be checked in any unexplained acid-base disorder ^[3]
Normal pH + ↓pCO₂ + ↓HCO₃⁻ = either chronic compensated resp alk OR mixed met acidosis + resp alk — use AG and clinical context to distinguish ^[10]
In paediatrics: resp alkalosis + hyperammonaemia → urea cycle defects ^[8]
Venous BG can screen for pH and HCO₃⁻ but cannot assess oxygenation — need ABG for pO₂ and A-a gradient ^[2]

Active Recall - Diagnostic Criteria, Algorithm and Investigations for Respiratory Alkalosis

^[1] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p.3–4, Compensatory mechanisms, Anion gap) ^[2] Senior notes: Ryan Ho Urogenital.pdf (p.34–35, Approach to Acid-base Disorders, Expected compensation, Three-step approach, VBG vs ABG interpretation) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (p.42, Salicylate poisoning — mixed resp alk + met acidosis case) ^[7] Senior notes: Learning_Points_All_Lectures.txt (Section 4, Respiratory Medicine — stepwise ABG interpretation) ^[8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.463–465, Inborn errors of metabolism — urea cycle defects vs organic acidaemias ABG patterns) ^[9] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.310, Rule of thumb — only chronic resp alkalosis may have complete compensation) ^[10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.85–90, Expected compensation "1-2-3-4" rule, mixed disorders table, causes of respiratory alkalosis) ^[11] Senior notes: Maksim Medicine Notes.pdf (p.213, ABG parameters, A-a gradient formula, compensation table) ^[12] Senior notes: Ryan Ho Chemical Path.pdf (p.27, Hypophosphataemia in respiratory alkalosis — Krebs cycle stimulation) ^[13] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p.3, Hypokalemia associated with alkalosis) ^[14] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (p.6, When to suspect renal tubular problems) ^[15] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.306, ARDS — ABG shows respiratory alkalosis) ^[16] Senior notes: Ryan Ho Respiratory.pdf (p.134–135, PE investigation findings — CXR, ECG, D-dimer)

The single most important concept in managing respiratory alkalosis is this: you treat the underlying cause, not the alkalosis itself. There is no "anti-alkalosis drug." The low pCO₂ is a consequence of hyperventilation, and hyperventilation is a consequence of something else. Fix that something else, and the pCO₂ normalises on its own.

This is fundamentally different from, say, managing metabolic acidosis where you might directly administer bicarbonate ^[17]. In respiratory alkalosis, the lungs are working too hard (or being driven too hard) — the fix is to address why.

The body compensates for acid-base disorders via: Lungs → immediate (hyperventilate, hypoventilate); Kidneys → takes several days ^[1]. In respiratory alkalosis, the kidneys are already compensating by excreting HCO₃⁻. Your job as a clinician is to remove the stimulus for hyperventilation.

Treatment Modalities by Aetiology

1. Treat the Underlying Cause (The Cornerstone)

This is the most important management principle and cannot be overemphasised.

The hyperventilation here is a physiological response to low pO₂. The treatment is to correct the hypoxaemia — once pO₂ is restored, the drive to hyperventilate diminishes.

Cause	Specific Treatment	Rationale
Pneumonia	Antibiotics (empiric then targeted), O₂ therapy, supportive care	Eliminate infection → resolve consolidation → improve V/Q matching → ↑pO₂ → ↓hyperventilatory drive
Pulmonary embolism	Anticoagulation (LMWH → warfarin/DOAC), thrombolysis if massive, supportive O₂	Resolve clot → restore perfusion to ventilated areas → ↓V/Q mismatch → ↑pO₂
Asthma (acute)	SABA (salbutamol) ± SAMA (ipratropium), IV/PO corticosteroids (hydrocortisone IV or prednisolone PO) ^[18]. Second-line: IV aminophylline (methylxanthine, PDE4 inhibitor) if no response ^[18]	Bronchodilation → ↓airway obstruction → improve gas exchange → ↓hypoxic drive. Caveat: aminophylline itself can stimulate the respiratory centre, so use judiciously
ARDS	Treat precipitant (sepsis, trauma), lung-protective mechanical ventilation (low tidal volume 6 mL/kg, PEEP), prone positioning	Minimise ventilator-induced lung injury while maintaining oxygenation
ILD	Immunosuppression (if inflammatory), antifibrotics (pirfenidone, nintedanib), supplemental O₂	Reduce disease progression; O₂ corrects hypoxaemia
Severe anaemia	Transfuse PRBCs, treat underlying cause (iron deficiency, bleeding)	Restore O₂ carrying capacity → ↓tissue hypoxia → ↓ventilatory drive
High altitude	Descent, supplemental O₂, acetazolamide (for prevention/treatment of altitude sickness)	Acetazolamide induces metabolic acidosis (carbonic anhydrase inhibitor → ↓HCO₃⁻ reabsorption in PCT) → counteracts the respiratory alkalosis and allows better acclimatisation

Oxygen therapy considerations:

Target SpO₂ 94–98% in most patients
In COPD patients: maintain SaO₂ = 88–92%; start with 24% Venturi mask or 1–2 L/min by nasal prongs; avoid high-dose O₂ to prevent removal of hypoxic drive ^[18]
Why is this relevant? A patient with COPD and acute pneumonia may present with T1RF and respiratory alkalosis initially. As you treat with O₂, be careful not to remove the hypoxic drive (in chronic CO₂ retainers), which could paradoxically convert them to T2RF with respiratory acidosis

High Yield — O₂ Therapy in Hypoxia-Driven Respiratory Alkalosis

Giving O₂ to a hypoxaemic patient with respiratory alkalosis corrects the stimulus for hyperventilation (low pO₂ at carotid body). As oxygenation improves, the drive to breathe excessively diminishes, pCO₂ rises back toward normal, and the alkalosis resolves. This is why supplemental O₂ is the first-line "treatment" for hypoxia-driven respiratory alkalosis.

Component	Treatment	Rationale
Source control	Drain abscesses, remove infected devices, debride necrotic tissue	Eliminate the source of endotoxin/cytokine release that drives respiratory centre stimulation
Antibiotics	Empiric broad-spectrum within 1 hour of recognition (e.g., piperacillin-tazobactam + vancomycin if MRSA risk), then narrow based on cultures	Kill the organisms producing the endotoxins
Fluid resuscitation	Crystalloid bolus (30 mL/kg initial)	Restore perfusion; if lactic acidosis coexists (mixed disorder), improving perfusion ↓lactate
Vasopressors	Noradrenaline if hypotensive despite fluids	Maintain MAP ≥ 65 mmHg to ensure organ perfusion
Monitoring	Serial ABGs, lactate, urine output	Track resolution of alkalosis and any concurrent metabolic acidosis

Respiratory alkalosis in sepsis is often the earliest lab abnormality — it typically resolves as sepsis is treated. If the patient worsens, respiratory alkalosis may progress to metabolic acidosis (lactic acidosis from shock) or T2RF (respiratory muscle fatigue).

Component	Treatment	Rationale
Chronic respiratory alkalosis in stable cirrhosis	No specific treatment needed — this is a well-compensated, chronic state	The kidney has already fully compensated; pH is normal. Treating the alkalosis directly would be harmful
Hepatic encephalopathy	Lactulose (↓NH₃ production/absorption), rifaximin (reduce gut bacteria that produce NH₃) ^[19]	NH₃ is a potent ventilatory stimulator → ↓NH₃ → ↓respiratory drive → pCO₂ normalises
Decompensated liver failure	Supportive ICU care, treat precipitants (infection, GI bleeding), consider liver transplant if King's College Criteria met ^[19]	Ultimate treatment of the failing liver removes the source of toxin accumulation
↑ICP in acute liver failure	Mannitol, hyperventilation, barbiturate coma (if refractory) ^[19]	Note: here, deliberate hyperventilation (maintaining resp alkalosis) is actually used therapeutically — ↓pCO₂ → cerebral vasoconstriction → ↓ICP. This is one of the few situations where you intentionally maintain respiratory alkalosis

Paradox — Deliberate Respiratory Alkalosis in Raised ICP

Mx of ↑ICP: mannitol, hyperventilation, barbiturate coma (if refractory) ^[19]. In acute liver failure with raised intracranial pressure, controlled hyperventilation is used therapeutically to lower pCO₂ → cerebral vasoconstriction → ↓cerebral blood volume → ↓ICP. This is a situation where you deliberately induce/maintain respiratory alkalosis. However, this must be done cautiously and temporarily (target pCO₂ ~30–35 mmHg), as prolonged severe hypocapnia causes excessive cerebral ischaemia.

Cause	Treatment
Stroke	Thrombolysis (if ischaemic, within window), thrombectomy, neurosurgical decompression (if haemorrhagic with mass effect)
Meningitis / Encephalitis	IV antibiotics (ceftriaxone + ampicillin ± dexamethasone for bacterial), acyclovir for HSV encephalitis
Brain tumour	Dexamethasone (↓peri-tumoural oedema), surgery ± radiotherapy ± chemotherapy
TBI	Neurosurgical management, ICP monitoring

Resolving the CNS pathology removes the direct stimulus on brainstem respiratory centres.

E. Drug / Toxin-Induced Respiratory Alkalosis

Treatment of aspirin toxicity: ^[3]

Resuscitation if unstable vitals
GI decontamination by activated charcoal to bind GI aspirin (most effective within 1–2 hours of ingestion)
Alkalinisation of serum and urine by sodium bicarbonate:
- Alkalinisation of serum → ionic trapping into blood → ↓intracellular salicylate level (salicylate in ionised form cannot cross cell membranes → trapped in blood → ↓tissue toxicity)
- Alkalinisation of urine → ionic trapping into tubular fluid → ↑salicylate excretion (same principle: ionised salicylate in urine cannot be reabsorbed → excreted)
Supplemental glucose if altered mental status (salicylates can cause neuroglycopaenia even with normal blood glucose, because they ↓CNS glucose transport)
Haemodialysis if: ^[3]
- Contraindication to NaHCO₃ (fluid overload)
- Renal failure (cannot excrete aspirin)
- Severe intoxication (salicylate level > 100 mg/dL, or refractory acidosis, or end-organ damage)

Why Alkalinise in Salicylate Poisoning — Not Acidify?

This seems counterintuitive: the patient already has respiratory alkalosis, so why make them more alkaline with bicarbonate? The answer lies in ionic trapping. Salicylic acid (pKa ~3.0) is a weak acid. In alkaline urine (pH > 7.5), salicylate becomes ionised (charged) and cannot be reabsorbed across the tubular epithelium back into blood → it stays in the urine and gets excreted. Similarly, alkaline blood keeps salicylate ionised in the intravascular space, preventing it from crossing into cells (especially the brain) where it does damage.

NEVER intubate a salicylate-poisoned patient without extreme caution: if you sedate and mechanically ventilate them, you may lose their compensatory hyperventilation → pCO₂ rises → pH drops → more salicylate becomes unionised → crosses into brain and other tissues → catastrophic worsening. If intubation is unavoidable, maintain their pre-intubation minute ventilation.

Drug	Management
Theophylline/methylxanthine toxicity	Stop drug, supportive care, activated charcoal (multi-dose), β-blockers for tachycardia, consider haemodialysis/haemoperfusion for severe toxicity
Progesterone	No treatment needed if physiological (pregnancy). Discontinue exogenous progesterone if causing symptoms

This is an ICU-specific problem and is entirely preventable.

Intervention	How It Works
↓Respiratory rate on ventilator	Fewer breaths per minute → ↓minute ventilation → ↑pCO₂
↓Tidal volume	Less volume per breath → ↓alveolar ventilation → ↑pCO₂
Add mechanical dead space	Inserting extra tubing between the ventilator circuit and the patient → patient rebreathes some CO₂ → ↑pCO₂. Used cautiously
Monitor with ABG	Check ABG 30–60 minutes after any ventilator adjustment to confirm pCO₂ is normalising

Check ABG 30–60 mins after initiation of non-invasive ventilation; do not delay intubation and mechanical ventilation if no improvement ^[18]. The same principle applies in reverse — after adjusting ventilator settings to correct respiratory alkalosis, recheck ABG to ensure you haven't over-corrected into respiratory acidosis.

Lung-protective ventilation (6 mL/kg tidal volume, as used in ARDS) may actually cause permissive hypercapnia (mild respiratory acidosis) — this is considered acceptable and even beneficial in ARDS management, representing the opposite end of the spectrum from respiratory alkalosis.

Intervention	Details	Rationale
Reassurance	Calm, authoritative explanation that symptoms (tingling, cramps, dizziness) are from overbreathing and are not dangerous	Breaks the cognitive spiral: anxiety → physical symptoms → ↑anxiety ^[6]. Patient understanding reduces fear
Breathing retraining	Coach slow, controlled breathing (e.g., diaphragmatic breathing, 6–8 breaths/min, prolonged exhalation)	Reduces minute ventilation → allows pCO₂ to normalise → symptoms resolve
Anxiolytics (short-term, acute)	Benzodiazepines (e.g., lorazepam 0.5–1 mg PO/SL/IV) for acute severe panic attacks	↓CNS excitability → ↓cortical drive for hyperventilation. Use with caution — not for chronic use
CBT (long-term)	Cognitive behavioural therapy for panic disorder/anxiety	Addresses "safety behaviours" and catastrophic cognitions that perpetuate the cycle ^[6]. Gold-standard psychological intervention
SSRIs/SNRIs (long-term)	Sertraline, paroxetine, venlafaxine for panic disorder	First-line pharmacotherapy for panic disorder if recurrent
Psychiatric referral	If recurrent episodes, significant functional impairment	Formal diagnosis and structured treatment plan

Paper Bag Rebreathing — Do NOT Recommend

The classic teaching of "breathe into a paper bag" to raise pCO₂ is no longer recommended in emergency settings. Reasons:

If the patient actually has a PE, pneumothorax, or cardiac disease causing their tachypnoea, reducing O₂ intake with a paper bag could be fatal
It may worsen anxiety in some patients
The same effect can be achieved more safely with coached slow breathing

Only consider in a clearly psychogenic setting where organic causes have been definitively excluded — and even then, breathing retraining is preferred.

2. Symptomatic Management of Electrolyte Consequences

Even as you treat the underlying cause, the electrolyte shifts caused by alkalosis may require direct correction:

Severity	Treatment	Rationale
Mild (paraesthesias only)	Reassurance + treat underlying cause; no calcium replacement needed	Resolving the alkalosis will restore normal ionised Ca²⁺ as pH normalises
Moderate (carpopedal spasm, Chvostek/Trousseau positive)	IV calcium gluconate 10% 10–20 mL over 10–20 min with cardiac monitoring	Directly repletes ionised Ca²⁺ to stop neuromuscular hyperexcitability. Use calcium gluconate (not chloride) peripherally because CaCl₂ causes tissue necrosis if extravasated
Severe (seizures, laryngospasm, arrhythmia)	IV calcium gluconate bolus + infusion, treat underlying cause urgently	Life-threatening emergency

Important: this is functional hypocalcaemia (total Ca usually normal, ionised Ca low due to pH-dependent albumin binding). Once the alkalosis resolves, ionised Ca normalises without needing ongoing calcium supplementation.

Severity	Treatment	Rationale
Mild (K⁺ 3.0–3.5)	PO KCl supplementation (40–80 mEq/day) if symptomatic	Replete K⁺ stores; alkalosis drives K⁺ intracellularly so total body K⁺ may actually be normal — correction of alkalosis alone may restore serum K⁺
Moderate (K⁺ 2.5–3.0)	PO or IV KCl (rate ≤ 20 mEq/hour via peripheral line, ≤ 40 mEq/hour via central line) with cardiac monitoring	ECG changes (ST depression, U waves) warrant more aggressive replacement
Severe (K⁺ < 2.5 or ECG changes or arrhythmia)	IV KCl via central line with continuous cardiac monitoring	Hypokalemia complications: generalised weakness (especially proximal musculature), respiratory failure, fatal arrhythmia ^[13]

Alkalosis very often is NOT the cause of hypoK, but rather its consequence, or a consequence of a common cause (e.g., vomiting, excessive renal K loss) ^[5]. In respiratory alkalosis specifically, the K⁺ shift is usually modest (~0.2–0.4 mEq/L per 0.1 pH rise) and rarely life-threatening on its own. But in mixed disorders (e.g., vomiting causing both metabolic alkalosis AND K⁺ loss), hypoK can be severe.

Usually mild and self-correcting as alkalosis resolves
Respiratory alkalosis → ↓cellular CO₂ → high cellular pH → stimulates Krebs cycle → consumption of phosphate ^[12]
Only treat if severe (PO₄ < 0.3 mmol/L) or symptomatic (muscle weakness, respiratory failure): IV sodium/potassium phosphate

3. Ventilatory Support — When and How

In respiratory alkalosis, the problem is too much ventilation, not too little. Ventilatory support is therefore directed at the underlying cause (e.g., O₂ for hypoxaemia, NIV for associated conditions), not at the alkalosis itself.

NIV may be relevant when respiratory alkalosis coexists with an underlying condition requiring ventilatory support:

Strongest evidence for NIV use: ^[20]

Acute COPD exacerbation with hypercapnic acidosis (PaCO₂ > 6.0 kPa or pH < 7.35)
Hypercapnic respiratory failure secondary to OHS, chest wall deformity, or neuromuscular disease
Cardiogenic pulmonary oedema
Facilitate weaning from invasive ventilation (especially in COPD)
Acute respiratory failure in immunocompromised patients

Contraindications to NIV: ^[20]

Absolute: Lack of spontaneous breathing/cardiopulmonary arrest; gasping; anatomical/functional airway obstruction; severe facial deformity/trauma/burns; GI bleeding or ileus
Relative: Haemodynamic instability; severe acidosis (pH < 7.15); inability to protect airway (GCS < 8); inability to cooperate in agitated status; excessive secretions; recent upper airway or GI surgery

Contraindications to NIV (from respiratory notes): ^[21]

Respiratory arrest and medical instability
Inability to protect airway and copious secretions
Uncooperative or agitated status and unfitting mask
Recent upper airway or GI surgery

Indications for invasive ventilation: ^[18]

Patients unable to tolerate or failed NIV
Impaired consciousness, massive aspiration, or unable to clear secretions
Severe haemodynamic instability without response to fluid and vasopressors
Severe ventricular arrhythmia, cardiac or respiratory arrest

When a patient with respiratory alkalosis requires intubation (e.g., for airway protection in severe encephalopathy), the ventilator settings must be carefully chosen to match the patient's pre-intubation minute ventilation. This is especially critical in salicylate poisoning (as discussed above).

When respiratory alkalosis is due to hyperammonaemia from urea cycle defects ^[8]:

Emergency treatment of ↑↑NH₃: ^[8]

Stop protein intake (including milk) — but only for a short period; prolonged ↓protein may ↑catabolism and worsen the condition
10% dextrose ± insulin/lipids to ↓catabolism — provides alternative energy substrate to prevent protein breakdown
Sodium benzoate/phenylbutyrate to ↓NH₃ — these are ammonia scavengers that provide alternative pathways for nitrogen excretion (benzoate conjugates with glycine → hippurate, excreted by kidney; phenylbutyrate conjugates with glutamine → phenylacetylglutamine, excreted by kidney)
Extracorporeal detoxification to ↓NH₃ if encephalopathy ± NH₃ > 300 mmol/L — haemodialysis or continuous veno-venous haemodiafiltration
Enzyme replacement to replenish deficient enzymes — e.g., arginine, citrulline, Carbaglu (carglumic acid for N-acetylglutamate synthase deficiency), carnitine (↑free-state transporter)
Forced diuresis to promote urinary excretion

Indications for haemodialysis (mnemonic: AEIOU): ^[17]

A — Acidosis: metabolic acidosis with pH < 7.1 refractory to bicarbonate infusion
E — Electrolyte imbalance: hyperK > 6.5 or rapidly rising K refractory to medical Rx
I — Intoxication: drug removal in overdose (salicylate, methanol, ethylene glycol, lithium)
O — Overload: fluid overload refractory to diuretics
U — Uraemia: features of uraemia (pericarditis, neuropathy, ↓mental status)

In the context of respiratory alkalosis, dialysis is relevant for:

Salicylate poisoning: removes salicylate directly when alkalinisation/charcoal are insufficient or contraindicated
Concurrent renal failure: if AKI develops (e.g., in sepsis), the kidney cannot compensate or excrete toxins
Concurrent severe metabolic acidosis: if mixed disorder with refractory metabolic acidosis

Aetiology	Primary Treatment	Supportive Measures
Pneumonia	Antibiotics, O₂	Electrolyte correction, fluids
PE	Anticoagulation ± thrombolysis, O₂	Monitoring, haemodynamic support
Asthma	Bronchodilators, steroids	O₂, monitor for fatigue → T2RF
Sepsis	Antibiotics, source control, fluids, vasopressors	Serial ABG, lactate, electrolytes
Liver failure	Treat precipitant, lactulose/rifaximin for encephalopathy, transplant	Hyperventilation for ↑ICP ^[19], electrolyte correction
Salicylate OD	Activated charcoal, NaHCO₃ (serum + urine alkalinisation), haemodialysis ^[3]	Do NOT suppress hyperventilation
CNS pathology	Treat underlying (surgery, antibiotics, steroids)	ICP management if needed
Over-ventilation	Adjust ventilator (↓RR, ↓TV, add dead space)	Recheck ABG 30–60 min
Anxiety / Panic	Reassurance, breathing retraining, anxiolytics, CBT/SSRIs long-term	Exclude organic causes first
Altitude	Descent, O₂, acetazolamide	Hydration
Pregnancy	None — physiological; pCO₂ 28–32 mmHg is normal	Reassurance
Urea cycle defects	Stop protein, dextrose, ammonia scavengers, dialysis ^[8]	Enzyme replacement, genetic counselling

High Yield Summary — Management of Respiratory Alkalosis

The treatment is the underlying cause — there is no "anti-alkalosis" drug for respiratory alkalosis
Hypoxia-driven: O₂ therapy is the first-line "anti-alkalosis" measure; treating the pulmonary pathology resolves the alkalosis
Salicylate poisoning: activated charcoal + NaHCO₃ alkalinisation + haemodialysis for severe cases ^[3]. NEVER suppress the patient's hyperventilation (it's keeping salicylate out of the brain)
Mechanical over-ventilation: ↓RR and ↓TV on the ventilator; recheck ABG in 30–60 min
Psychogenic: reassurance, breathing retraining, anxiolytics acutely, CBT/SSRIs long-term. Paper bag rebreathing is no longer recommended in emergency settings
Electrolyte consequences: IV Ca gluconate for symptomatic ↓iCa²⁺; KCl for significant hypoK; phosphate replacement rarely needed
Deliberate respiratory alkalosis is used therapeutically for ↑ICP in acute liver failure: hyperventilation → ↓pCO₂ → cerebral vasoconstriction → ↓ICP ^[19]
Chronic compensated respiratory alkalosis (e.g., stable cirrhosis, pregnancy): no treatment needed — the kidney has fully compensated
Haemodialysis indications (AEIOU): Acidosis, Electrolyte, Intoxication, Overload, Uraemia ^[17] — relevant for salicylate poisoning and concurrent renal failure

Active Recall - Management of Respiratory Alkalosis

^[1] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p.2–3, Compensation mechanisms) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (p.42, Salicylate poisoning); Ryan Ho Urogenital.pdf (p.48, Aspirin toxicity treatment) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p.18, Footnote 20 — alkalosis is often not the cause of hypoK) ^[6] Senior notes: Ryan Ho Psychiatry.pdf (p.173, Cognitive theory of anxiety spiral) ^[8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.463–465, Emergency treatment of hyperammonaemia, urea cycle defects) ^[12] Senior notes: Ryan Ho Chemical Path.pdf (p.27, Hypophosphataemia in respiratory alkalosis) ^[13] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p.3, Hypokalemia complications) ^[17] Senior notes: Ryan Ho Critical Care.pdf (p.26, Haemodialysis indications AEIOU, management of metabolic acidosis with NaHCO₃) ^[18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.226–228, Acute COPD exacerbation management — O₂ therapy, NIV, invasive ventilation indications) ^[19] Senior notes: Ryan Ho GI.pdf (p.207, Acute liver failure management — hyperventilation for ↑ICP, lactulose, rifaximin) ^[20] Lecture slides: Handbook of Internal Medicine 2024.pdf (p.421, NIV evidence levels and contraindications) ^[21] Senior notes: Ryan Ho Respiratory.pdf (p.33, NIV contraindications and use)

Complications of Respiratory Alkalosis

The complications of respiratory alkalosis arise from the downstream effects of low pCO₂ (hypocapnia) and elevated pH (alkalaemia) on multiple organ systems. They can be broadly divided into:

Direct consequences of the alkalosis and hypocapnia (electrolyte shifts, cerebral vasoconstriction, impaired O₂ delivery)
Complications of the renal compensation (chronic changes)
Complications of the underlying cause (which often dominate the clinical picture)

It is important to understand that isolated respiratory alkalosis is rarely fatal on its own — lethal pH levels are < 7.1 or > 7.7 ^[1]^[22]. However, even moderate alkalosis produces clinically significant complications that can worsen the patient's overall condition, and in critically ill patients these effects compound other organ dysfunction.

1. Neuromuscular Complications

These are the most immediately apparent complications and often what prompts the patient to seek medical attention.

Mechanism: Alkalosis → ↓ionised Ca²⁺ (Ca²⁺ binds more tightly to negatively-charged albumin at higher pH) → lowered threshold for neuronal and muscular depolarisation → spontaneous firing of sensory and motor nerves
Clinical features:
- Perioral numbness and acral paraesthesias (tingling around the mouth, fingertips, toes) — sensory neurons fire spontaneously
- Carpopedal spasm — involuntary hand/foot contraction ("main d'accoucheur" posture)
- Positive Chvostek's and Trousseau's signs — latent tetany elicited on examination
Severity: Usually self-limiting if the alkalosis resolves; severe or prolonged alkalosis can progress to generalised muscle spasm
Why perioral specifically? The sensory nerve endings around the mouth (branches of CN V) have a particularly low threshold for depolarisation, making this region the earliest and most sensitive to detect ↓ionised Ca²⁺

Mechanism: Two synergistic factors:
1. Cerebral vasoconstriction from ↓pCO₂ → cerebral ischaemia → lowered seizure threshold
2. ↓Ionised Ca²⁺ → neuronal hyperexcitability → lowered seizure threshold
Clinical significance: Seizures from respiratory alkalosis alone are uncommon but can occur when pH exceeds ~7.6 or when superimposed on pre-existing epilepsy or CNS pathology
Type: Usually generalised tonic-clonic, but focal seizures can occur depending on the degree of regional cerebral ischaemia

Mechanism: Hypokalemia complications include generalised weakness (especially of the proximal musculature), respiratory failure, and fatal arrhythmia ^[13]. The hypokalaemia of alkalosis (K⁺ shifts intracellularly) reduces the resting membrane potential of muscle cells, impairing their contractile function
Paradox: alkalosis causes both tetany (from ↓iCa²⁺ → hyperexcitability) and weakness (from ↓K⁺ → impaired contraction). These are not contradictory — they affect different pathways. Tetany is from nerve hyperexcitability at the neuromuscular junction level; weakness is from impaired muscle cell repolarisation

2. Cardiovascular Complications

Mechanism: Alkalosis produces multiple pro-arrhythmic changes:
- Hypokalaemia → flattened T waves, U waves, ST depression, prolonged QT → predisposition to re-entrant tachycardias, ventricular ectopics, and potentially torsades de pointes (TdP)
- ↓Ionised Ca²⁺ → prolonged QT interval (Ca²⁺ is needed for the plateau phase of the cardiac action potential; ↓iCa²⁺ prolongs it)
- Alkalosis directly alters cardiac ion channel kinetics (shifts voltage-gating thresholds)
Clinical significance: Particularly dangerous in patients with pre-existing cardiac disease, on digoxin (alkalotic hypokalaemia potentiates digoxin toxicity), or with concurrent electrolyte abnormalities
Both hypo- and hyperkalemia have lethal consequences ^[14]^[22] — in the context of respiratory alkalosis, the hypokalaemia is usually modest, but in combination with other causes of K⁺ loss (vomiting, diuretics), it can become life-threatening

Hypokalemia: U wave, flat T wave, long QTc — these ECG changes should be actively monitored in patients with significant respiratory alkalosis ^[13]

Mechanism: Alkalosis causes smooth muscle constriction in coronary arteries → ↓coronary blood flow → risk of myocardial ischaemia, especially in patients with pre-existing coronary artery disease
In severe alkalosis (pH > 7.55), this can precipitate angina or even acute coronary syndrome
Peripheral vasoconstriction also occurs, though this is usually clinically less significant than the coronary effects

Mechanism: Severe alkalosis → ↓cardiac contractility (direct effect of extreme pH on myocardial function) + vasodilation in some vascular beds → reduced cardiac output
This is primarily seen at lethal pH levels (> 7.7) ^[1] and is a pre-terminal event

3. Central Nervous System Complications

Mechanism: CO₂ is a potent cerebral vasodilator. When pCO₂ drops, cerebral arterioles constrict. This is a well-characterised physiological response:
- Every 1 mmHg drop in pCO₂ → approximately 2% decrease in cerebral blood flow (CBF)
- At pCO₂ of ~20 mmHg, CBF can be reduced by 35–40% compared to baseline
Clinical consequences:
- Lightheadedness, dizziness, visual disturbances (blurred vision, tunnel vision)
- Impaired concentration, confusion
- Syncope or near-syncope
- In extreme cases: ischaemic cerebral damage (especially in patients with pre-existing cerebrovascular disease)
Clinical relevance: This is why deliberate hyperventilation for ↑ICP must be used cautiously — while it effectively lowers ICP by reducing cerebral blood volume, prolonged severe hypocapnia (pCO₂ < 25 mmHg) can cause cerebral ischaemia and worsen neurological outcome

Ranges from mild confusion to obtundation
In critically ill patients (e.g., sepsis with respiratory alkalosis), it may be difficult to separate the CNS effects of the alkalosis from those of the underlying disease

4. Respiratory Complications

This is one of the most clinically important complications, especially in critically ill patients.

Mechanism: Alkalosis → ↑Hb affinity for O₂ → leftward shift of the O₂-Hb dissociation curve → Hb holds onto O₂ more tightly at the tissue level → ↓O₂ release to tissues
Clinical significance: Even though PaO₂ may be normal or elevated (especially in psychogenic hyperventilation where PaO₂ can be supranormal), tissue oxygen delivery is impaired. This is a "hidden hypoxia" — the blood looks well-oxygenated on ABG and pulse oximetry, but the tissues are receiving less O₂ than expected
This effect compounds other causes of tissue hypoxia (e.g., in sepsis with both respiratory alkalosis AND lactic acidosis, the leftward shift further worsens an already compromised oxygen delivery)

Mechanism: Hypocapnia causes airway smooth muscle constriction → ↑airway resistance
Clinical significance: In patients with pre-existing asthma or reactive airway disease, this can worsen bronchospasm. It can also paradoxically worsen dyspnoea, perpetuating the cycle of hyperventilation (especially in psychogenic hyperventilation)

If the cause of hyperventilation persists (e.g., worsening pneumonia, PE), the respiratory muscles may eventually fatigue
This converts the initial respiratory alkalosis picture into Type 2 respiratory failure (T2RF): ↓pO₂ + ↑pCO₂ → respiratory acidosis ^[5]
Hypoxia initially leads to increased RR and respiratory alkalosis; eventually respiratory muscle fatigue will lead to respiratory acidosis ^[23]
Clinical pearl: In acute asthma, a "normalising" pCO₂ (from low → normal) is actually a danger sign — it means the patient is tiring and can no longer maintain the compensatory hyperventilation. The next step is a rapidly rising pCO₂, respiratory acidosis, and potentially respiratory arrest

High Yield — Normalising pCO₂ in Acute Asthma Is a Danger Sign

A patient with an acute severe asthma exacerbation who initially has respiratory alkalosis (low pCO₂) and whose pCO₂ is now rising toward normal is NOT improving. They are fatiguing. A normal or rising pCO₂ in the setting of acute asthma should prompt consideration of ICU transfer and preparation for intubation.

5. Electrolyte and Metabolic Complications

Mechanism: Alkalosis → H⁺ leaves cells (to buffer the extracellular alkalosis) → K⁺ enters cells (to maintain electroneutrality) → ↓serum K⁺
Approximate shift: ~0.2–0.4 mEq/L drop per 0.1 unit pH rise
Hypokalemia is usually associated with alkalosis ^[13]
Complications of hypokalaemia: generalised weakness (especially proximal musculature), respiratory failure, fatal arrhythmia ^[13]
In respiratory alkalosis alone, the K⁺ shift is usually modest. But if combined with other causes of K⁺ loss (diarrhoea, diuretics, vomiting), significant life-threatening hypokalaemia can develop

Mechanism: Respiratory alkalosis results in ↓cellular CO₂. The resultant high cellular pH stimulates Krebs cycle, resulting in consumption of phosphate ^[12]. Additionally, alkalosis stimulates glycolysis (activates phosphofructokinase), which also consumes intracellular phosphate
Clinical significance: Usually mild and self-limiting, but severe hypophosphataemia (PO₄ < 0.3 mmol/L) can cause:
- Muscle weakness (including respiratory muscles → can worsen respiratory failure)
- Impaired myocardial contractility
- Rhabdomyolysis (rare)
- Haemolytic anaemia (↓RBC 2,3-DPG → fragile RBCs)
Most commonly seen in patients who are already phosphate-depleted (malnourished, alcoholics, refeeding syndrome)

Mechanism: ↑pH → ↑negative charges on albumin → ↑Ca²⁺ binding → ↓free/ionised Ca²⁺
Total calcium remains normal — this is NOT true hypocalcaemia but a redistribution effect
Resolves completely when pH normalises
Complications: as above (paraesthesias, tetany, seizures, long QT, arrhythmias)

Mechanism: Alkalosis stimulates glycolysis by activating phosphofructokinase → ↑pyruvate production → ↑lactate generation. Additionally, the leftward shift of the O₂-Hb curve means tissues release less O₂ → tissue hypoxia → anaerobic metabolism → lactate production
Clinical significance: This creates a paradoxical situation where respiratory alkalosis can generate a concurrent metabolic acidosis. In sepsis, this compounds the lactic acidosis already present from poor perfusion
Mixed disorders: M. acidosis + R. alkalosis → salicylate overdose, sepsis, liver + renal failure ^[11] — the lactic acidosis in sepsis may be partly driven by the alkalosis itself

6. Renal Complications (from Chronic Compensation)

In chronic respiratory alkalosis, the kidney dumps HCO₃⁻ as compensation → serum HCO₃⁻ drops to 12–18 mmol/L
Clinical significance: The patient now has a reduced buffer reserve. If they develop an acute metabolic acidosis (e.g., sepsis with lactic acidosis, acute kidney injury), they have less buffering capacity to withstand the acid load → pH drops more precipitously than it would in someone with normal HCO₃⁻ stores
This is particularly relevant in cirrhotic patients (chronic respiratory alkalosis) who develop acute-on-chronic liver failure with lactic acidosis — they are extremely vulnerable to acute pH drops

As the kidney excretes HCO₃⁻, it retains Cl⁻ to maintain electroneutrality → mild hyperchloraemic state
Usually clinically insignificant but contributes to a non-anion-gap metabolic acidosis component that can complicate ABG interpretation

In clinical practice, the complications of the underlying cause usually dominate over those of the alkalosis itself. These are not strictly "complications of respiratory alkalosis" but are essential to consider:

Underlying Cause	Major Complications
Sepsis	Multi-organ failure, DIC, ARDS, death
PE	RV failure, obstructive shock, death
Hepatic failure	Hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, coagulopathy
Salicylate poisoning	Metabolic acidosis (late stage), non-cardiac pulmonary oedema, cerebral oedema, coma, death ^[3]
Panic disorder	Functional impairment, agoraphobia, depression (long-term psychiatric sequelae)
Mechanical over-ventilation	Haemodynamic compromise (↓venous return from excessive positive pressure), barotrauma, ventilator-induced lung injury

8. Post-Hyperventilation Complications — When Respiratory Alkalosis Resolves

If the cause of hyperventilation is abruptly removed (e.g., sedation of an anxious patient, correction of ventilator settings), pCO₂ rises rapidly
However, the renal compensation (↓HCO₃⁻) takes days to reverse → the patient now has a low HCO₃⁻ with a rising pCO₂ → pH drops below normal → transient metabolic acidosis or mixed disorder
This is analogous to post-hypercapnic metabolic alkalosis (where rapid correction of chronic respiratory acidosis unmasks the renal compensation as a primary alkalosis ^[22]) — but in reverse

During the alkalosis, K⁺ was shifted intracellularly. As pH normalises, K⁺ shifts back out → if K⁺ was aggressively replaced during the alkalosis, the patient may now be at risk of hyperkalaemia as the intracellular K⁺ returns to the ECF
Conversely, if K⁺ was not adequately replaced and the underlying cause also depleted total body K⁺ (e.g., vomiting), the patient may remain hypokalaemic

Organ System	Complication	Mechanism
Neuromuscular	Paraesthesias, tetany, carpopedal spasm	↓Ionised Ca²⁺
Neuromuscular	Seizures	↓iCa²⁺ + cerebral hypoperfusion
Neuromuscular	Muscle weakness	Hypokalaemia
CNS	Dizziness, confusion, syncope	Cerebral vasoconstriction from hypocapnia
CVS	Arrhythmias (VT, TdP, AF)	Hypokalaemia + ↓iCa²⁺ → prolonged QT
CVS	Coronary vasoconstriction → ischaemia	Direct effect of alkalosis on coronary smooth muscle
Respiratory	↓Tissue O₂ delivery	Leftward shift O₂-Hb curve (Bohr effect)
Respiratory	Bronchoconstriction	Hypocapnia → airway smooth muscle constriction
Respiratory	Progression to T2RF	Respiratory muscle fatigue
Metabolic	Hypokalaemia	Intracellular K⁺ shift
Metabolic	Hypophosphataemia	↑Glycolysis and Krebs cycle activity consume PO₄
Metabolic	Functional hypocalcaemia	↑Albumin-Ca²⁺ binding at high pH
Metabolic	Paradoxical lactic acidosis	↑Glycolysis + ↓tissue O₂ delivery
Renal	↓HCO₃⁻ buffer reserve (chronic)	Renal compensation → bicarbonate wasting
Post-correction	Rebound acidosis	Persistent low HCO₃⁻ after pCO₂ normalises

High Yield Summary — Complications of Respiratory Alkalosis

Neuromuscular: paraesthesias, carpopedal spasm, and tetany from ↓ionised Ca²⁺ (total Ca normal); seizures from cerebral hypoperfusion + ↓iCa²⁺
Cardiovascular: arrhythmias (prolonged QT from ↓iCa²⁺ and ↓K⁺ → risk of TdP); coronary vasoconstriction → ischaemia in susceptible patients
CNS: cerebral vasoconstriction → ↓CBF up to 35-40% → lightheadedness, syncope, confusion
Tissue oxygenation: leftward shift of O₂-Hb dissociation curve → "hidden hypoxia" — tissues receive less O₂ despite adequate PaO₂
Hypokalaemia complications: generalised weakness, respiratory failure, fatal arrhythmia ^[13]
Hypophosphataemia from ↑Krebs cycle activity consuming phosphate ^[12]
In acute asthma: normalising pCO₂ (from low toward normal) = DANGER SIGN of respiratory muscle fatigue → impending T2RF
Chronic respiratory alkalosis reduces HCO₃⁻ buffer reserve → the patient is vulnerable to superimposed metabolic acidosis
Post-correction: risk of rebound acidosis and K⁺ shifts — monitor electrolytes closely
Lethal pH levels: < 7.1 or > 7.7 ^[1] — while respiratory alkalosis alone rarely reaches pH > 7.7, combined with metabolic alkalosis it can approach this

Active Recall - Complications of Respiratory Alkalosis

References

^[1] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p.2, Lethal pH levels) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (p.42, Salicylate poisoning complications) ^[5] Senior notes: Ryan Ho Fundamentals.pdf (p.230, Respiratory failure types and clinical features); Ryan Ho Respiratory.pdf (p.29, T1RF and T2RF causes) ^[11] Senior notes: Maksim Medicine Notes.pdf (p.213, Mixed disorders — M. acidosis + R. alkalosis combinations) ^[12] Senior notes: Ryan Ho Chemical Path.pdf (p.27, Hypophosphataemia in respiratory alkalosis — Krebs cycle mechanism) ^[13] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p.3, Hypokalemia complications) ^[14] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (p.6, Both hypo and hyperK have lethal consequences) ^[22] Lecture slides: Introduction-kidney-Ix.pdf (p.27); Nephrology - ntroduction to Renal Investigation.pdf (p.27, Acid-base disorders definitions, lethal pH) ^[23] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.92, Causes of respiratory alkalosis — hypoxic hyperventilation progression)

High Yield Summary

Respiratory alkalosis = hyperventilation → ↓pCO₂ → ↑pH — the most common acid-base disturbance in hospitalised patients
Chronic respiratory alkalosis is the ONLY acid-base disorder where compensation may be complete (normal pH) — because the kidney can effectively dump HCO₃⁻ over days
Key causes to remember: Anxiety/hyperventilation syndrome, pneumonia, PE, sepsis (often earliest sign!), liver failure (HBV cirrhosis — very HK-relevant), salicylate poisoning, pregnancy, mechanical over-ventilation
Salicylate poisoning = mixed respiratory alkalosis + metabolic acidosis (unique combination)
Symptoms arise from: ↓ionised Ca²⁺ (paraesthesias, tetany, Chvostek/Trousseau signs), cerebral vasoconstriction (dizziness, syncope, confusion), and ↓K⁺ (arrhythmias)
Compensation formulas: Acute ΔHCO₃⁻ = 2 per 10 mmHg ΔpCO₂; Chronic ΔHCO₃⁻ = 4–5 per 10 mmHg ΔpCO₂
Never dismiss tachypnoea as "just anxiety" — always rule out PE, pneumothorax, DKA, and other serious causes
Alkalosis shifts K⁺ intracellularly and ↑Hb-O₂ affinity (leftward Bohr shift) → impairs tissue O₂ delivery

High Yield Summary — Differential Diagnosis of Respiratory Alkalosis

First step: confirm it's primary respiratory alkalosis, not compensatory hyperventilation for metabolic acidosis (look at pH direction)
Use A-a gradient: elevated → pulmonary pathology (PE, pneumonia, ILD); normal → non-pulmonary (psychogenic, CNS, liver, drugs)
Top dangerous causes to never miss: PE, sepsis (earliest sign!), salicylate poisoning, CNS pathology
Salicylate poisoning = mixed respiratory alkalosis + HAGMA — suspect in any acid-base disorder of unknown origin ^[3]
PE ABG: hypoxaemia + hypocapnia + respiratory alkalosis + ↑A-a gradient + Type I respiratory failure ^[4]
Liver failure (HBV cirrhosis in HK) → chronic respiratory alkalosis, often fully compensated
Psychogenic is a diagnosis of EXCLUSION — must have normal pO₂ and normal A-a gradient
In paediatrics: unexplained respiratory alkalosis + encephalopathy → think urea cycle defects (hyperammonaemia) ^[8]
Mixed disorders: use compensation formulae and "not up, not down" rule to unmask ^[2]

High Yield Summary — Diagnosis of Respiratory Alkalosis

ABG is the gold standard: ↓pCO₂ + ↑pH (acute) or normal pH (chronic) + ↓HCO₃⁻
Use the "1-2-3-4 rule": acute resp alk compensation = 2 mmol/L ↓HCO₃⁻ per 10 mmHg ↓pCO₂; chronic = 4 mmol/L ^[2]^[10]
Always check if compensation is appropriate — if HCO₃⁻ lower than expected → mixed with met acidosis; if higher → mixed with met alkalosis ^[2]
A-a gradient separates pulmonary (↑) from non-pulmonary (normal) causes
Calculate anion gap to unmask hidden HAGMA (especially salicylate poisoning) ^[1]^[3]
Salicylate level should be checked in any unexplained acid-base disorder ^[3]
Normal pH + ↓pCO₂ + ↓HCO₃⁻ = either chronic compensated resp alk OR mixed met acidosis + resp alk — use AG and clinical context to distinguish ^[10]
In paediatrics: resp alkalosis + hyperammonaemia → urea cycle defects ^[8]
Venous BG can screen for pH and HCO₃⁻ but cannot assess oxygenation — need ABG for pO₂ and A-a gradient ^[2]

High Yield Summary — Management of Respiratory Alkalosis

The treatment is the underlying cause — there is no "anti-alkalosis" drug for respiratory alkalosis
Hypoxia-driven: O₂ therapy is the first-line "anti-alkalosis" measure; treating the pulmonary pathology resolves the alkalosis
Salicylate poisoning: activated charcoal + NaHCO₃ alkalinisation + haemodialysis for severe cases ^[3]. NEVER suppress the patient's hyperventilation (it's keeping salicylate out of the brain)
Mechanical over-ventilation: ↓RR and ↓TV on the ventilator; recheck ABG in 30–60 min
Psychogenic: reassurance, breathing retraining, anxiolytics acutely, CBT/SSRIs long-term. Paper bag rebreathing is no longer recommended in emergency settings
Electrolyte consequences: IV Ca gluconate for symptomatic ↓iCa²⁺; KCl for significant hypoK; phosphate replacement rarely needed
Deliberate respiratory alkalosis is used therapeutically for ↑ICP in acute liver failure: hyperventilation → ↓pCO₂ → cerebral vasoconstriction → ↓ICP ^[19]
Chronic compensated respiratory alkalosis (e.g., stable cirrhosis, pregnancy): no treatment needed — the kidney has fully compensated
Haemodialysis indications (AEIOU): Acidosis, Electrolyte, Intoxication, Overload, Uraemia ^[17] — relevant for salicylate poisoning and concurrent renal failure

High Yield Summary — Complications of Respiratory Alkalosis

Neuromuscular: paraesthesias, carpopedal spasm, and tetany from ↓ionised Ca²⁺ (total Ca normal); seizures from cerebral hypoperfusion + ↓iCa²⁺
Cardiovascular: arrhythmias (prolonged QT from ↓iCa²⁺ and ↓K⁺ → risk of TdP); coronary vasoconstriction → ischaemia in susceptible patients
CNS: cerebral vasoconstriction → ↓CBF up to 35-40% → lightheadedness, syncope, confusion
Tissue oxygenation: leftward shift of O₂-Hb dissociation curve → "hidden hypoxia" — tissues receive less O₂ despite adequate PaO₂
Hypokalaemia complications: generalised weakness, respiratory failure, fatal arrhythmia ^[13]
Hypophosphataemia from ↑Krebs cycle activity consuming phosphate ^[12]
In acute asthma: normalising pCO₂ (from low toward normal) = DANGER SIGN of respiratory muscle fatigue → impending T2RF
Chronic respiratory alkalosis reduces HCO₃⁻ buffer reserve → the patient is vulnerable to superimposed metabolic acidosis
Post-correction: risk of rebound acidosis and K⁺ shifts — monitor electrolytes closely
Lethal pH levels: < 7.1 or > 7.7 ^[1] — while respiratory alkalosis alone rarely reaches pH > 7.7, combined with metabolic alkalosis it can approach this

Respiratory Alkalosis

References

Definition

The Henderson-Hasselbalch Equation — First Principles

Epidemiology

Risk Factors

Anatomy and Physiology of CO₂ Homeostasis

1. CO₂ Production

2. CO₂ Elimination — The Respiratory System

3. Central Control of Ventilation

4. Renal Compensation (The Kidney's Role)

Etiology (with Focus on Hong Kong Context)

Classification by Mechanism

Detailed Etiological Categories

A. Hypoxia-Driven Hyperventilation (via peripheral chemoreceptors)

B. Direct Central Stimulation of Respiratory Centre

C. Pulmonary Receptor Stimulation

D. Psychogenic / Voluntary

E. Iatrogenic

F. Miscellaneous

Classification

1. Acute Respiratory Alkalosis

2. Chronic Respiratory Alkalosis

Clinical Features

A. Symptoms (with pathophysiological basis)

B. Signs (with pathophysiological basis)

C. Key Electrolyte Shifts in Respiratory Alkalosis

D. Hyperventilation Syndrome — A Special Clinical Entity

E. Effects on Organ Systems — Why Respiratory Alkalosis Matters

ABG Interpretation — Expected Values in Respiratory Alkalosis

Compensation Formulas (Exam Essential)

Summary of Pathophysiology — Integrated View

Active Recall - Respiratory Alkalosis (Definition through Clinical Features)

References

Differential Diagnosis of Respiratory Alkalosis

Step 0: Is This Primary Respiratory Alkalosis or Compensatory Hyperventilation?

Step 1: Confirm the Primary Respiratory Alkalosis

Step 2: Differential Diagnosis of the Underlying Cause

Detailed Differential Diagnosis Table

A. Hypoxia-Driven Causes (pO₂ < 60 mmHg → peripheral chemoreceptor activation)

B. Non-Hypoxic, Organic Causes (pO₂ normal — direct central or reflex stimulation)

C. Psychogenic / Functional Causes (Diagnosis of Exclusion)

D. Iatrogenic Causes

E. Mixed Acid-Base Disorders Mimicking or Coexisting with Respiratory Alkalosis

Special Paediatric Differential Considerations

Systematic Differential Diagnosis — Summary Table

How to Use the A-a Gradient in the Differential

Clinical Approach — Putting It Together

Active Recall - Differential Diagnosis of Respiratory Alkalosis

References

Diagnostic Criteria for Respiratory Alkalosis

ABG Diagnostic Criteria

Distinguishing Acute vs Chronic

Detecting Mixed Disorders — The Key Diagnostic Step

Worked Example — Salicylate Poisoning (Classic Exam Case)

Diagnostic Algorithm

Investigation Modalities — Systematic Approach

A. Confirming the Acid-Base Disorder

1. Arterial Blood Gas (ABG) — The Gold Standard

2. Serum Electrolytes

3. Anion Gap

B. Identifying the Underlying Aetiology

4. Pulse Oximetry / Oxygen Saturation

5. Chest X-Ray (CXR)

6. ECG

7. Blood Tests — Targeted to Aetiology

8. Advanced Imaging — For Specific Aetiologies

9. Specific Paediatric Investigations

C. Putting It All Together — Investigation Summary Table

Interpreting Normal pH with Respiratory Alkalosis — A Common Exam Scenario

Active Recall - Diagnostic Criteria, Algorithm and Investigations for Respiratory Alkalosis

References

Management of Respiratory Alkalosis — Core Principle

Management Algorithm

Treatment Modalities by Aetiology

1. Treat the Underlying Cause (The Cornerstone)

A. Hypoxia-Driven Respiratory Alkalosis

B. Sepsis / SIRS

C. Hepatic Failure / Cirrhosis

D. CNS Pathology