BJA Education, 22(10): 396e401 (2022)

doi: 10.1016/j.bjae.2022.06.003
Advance Access Publication Date: 18 August 2022

Matrix codes: 1A01,

2A12, 3J00

Acidebase balance: a review of normal physiology

I. Shaw1,* and K. Gregory2
1
Sheffield Teaching Hospitals NHS Trust, Sheffield, UK and 2University Hospitals of Birmingham NHS
Foundation Trust, Birmingham, UK
*Corresponding author: [email protected]

Keywords: acidebase equilibrium; buffers; physiology

Learning objectives Key points

By reading this article you should be able to:
Alterations in pH have a profound effect on

Explain the development of critical care services physiological function.
enabled by advances in technology.
The body uses buffer systems to reduce the

Define an acidosis and how this affects normal impact of an acute acid load.
physiology.
Bicarbonate is the most important buffer and

Describe the major buffer systems in the body functions in an open system.
and the difference between ‘open’ and ‘closed’
Fine control of acidebase status is brought about
systems. by the kidneys and liver.

Discuss the role of the kidney and liver in dealing
with an acid load. cyanosis. The mortality was initially more than 90%. It was
noted that patients died with an increased total carbon di-
oxide in their blood. At the time this was thought to indicate
It is quite apt that this article, reviewing the normal physi-
that the patients had a metabolic alkalosis. Bjorn Ibsen, a
ology of acidebase balance, was written during the COVID-19
Danish anaesthetist, suggested that in fact the patients died
epidemic of 2020e22: the importance of acidebase became
of lack of ventilation, this was confirmed with the assistance
clear during the polio epidemic of the early 1950s that centred
of Poul Astrup, director of the clinical laboratory, who using
in Blegdamshospital, Copenhagen. At this time new technol-
the recently developed pH electrode was able to prove that
ogy and knowledge came together to achieve medical
patients were acidaemic.
advances.
Working with Henry Lassen chief physician at the hospital,
The onset of the epidemic saw a high number of patients
Ibsen built a team including anaesthetists, surgeons, clinical
developing severe respiratory paralysis with bulbar polio-
physiologists, nurses and medical students. Patients had a
myelitis. Management strategies focused on supporting the
tracheostomy performed and were hand bagged by the stu-
patient’s breathing, using negative pressure ventilators and
dents, sometimes for weeks. For the first time blood gas
adding supplementary oxygen guided by the presence of
analysis of pH and PCO2 were used clinically to guide care. The
modern Critical Care was born.1
Today, the assessment of acidebase status continues to
be pivotal in our management of critically ill patients.
Ian Shaw FRCA is a consultant anaesthetist at Sheffield Teaching Measurement of lactate is an essential part of assessing
Hospitals NHS Trust. He has been an examiner for the Primary FRCA patients with sepsis. Although lactate is not a direct mea-
and section lead for physiology. He has also contributed to the RCOA sure of tissue perfusion, it may be an indicator of anaerobic
e-Learning for Health sessions and authored the physiology revision respiration within hypoxic tissues; or a result of accelerated
guide. glycolysis driven by b-adrenergic stimulation or from he-
patic dysfunction. Regardless of the aetiology, RCTs evalu-
Katherine Gregory FRCA is a retired consultant anaesthetist
ating lactate-guided resuscitation have shown a reduced
formerly of University Hospitals of Birmingham NHS Foundation
mortality.2
Trust. She was an examiner for the Primary FRCA and has lectured
on the RCoA Primary Masterclass.

Accepted: 11 June 2022

© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: [email protected]

396
 Acidebase balance

What is acidosis and what is its relevance? Cao2 ¼ 1.34  Hb  Sao2 þ (0.025  Po2) ml L1 (normally
200 ml L1 blood)
pH¼ elog10[Hþ]
The venous point of O2 is 5.3 kPa and 70% saturated at pH
7.4. This relates to an arterio-venous (a-v) difference of 60 ml
The normal blood pH is 7.35e7.45; this relates to a
L1. In metabolically active tissues (such as exercising mus-
hydrogen ion concentration [Hþ] of 35e45 nmol L1. An
cles), there is a reduced pH closer to 7.2; here the saturation
acidosis is defined as a pH below 7.35. pH above 7.45 is an
approaches 55%, and the a-v difference is now 90 ml L1. In
alkalosis. Although the [Hþ] (in nmol L1) has a concentration
essence there is an extra 30 ml O2 per litre cardiac output
1/1,000,000 of other common ions (Naþ 135 mmol L1, Cle 105
delivered to the tissues (Fig. 1).
mmol L1), it gains a major significance as the chemical re-
actions of many biological processes, enabled by enzymatic
proteins, are highly dependent on pH. Balance between acidebase production and
For example during strenuous exercise, lactic acid accu-
clearance
mulates in skeletal muscle. This is a strong acid, with a pKa of
3.8, that rapidly dissociates to lactatee and Hþ ions, leading to The body produces approximately 13 mol day1 of acid. This is
a reduction in the intracellular pH. This lowers the concen- made up of volatile acids from the production of CO2 (13,000
tration of free Ca2þ within the sarcomere available to react mmol day1 or 0.5 kg for those who want to carbon offset) and
with troponin and reduces the number of actinemyosin in- non-volatile acids (80 mmol day1). The non-volatile acids are
teractions. This, in turn, leads to a reduction in the force of subclassified as organic acids (lactate, free fatty acids and b-
contraction of the muscle. There is a matching decrease on hydroxybutyrate) and inorganic acids (sulphuric, phosphoric
cardiac muscle contractility in laboratory studies; however, acid).
this is not replicated in all clinical studies and this is thought In normal homeostasis there is an impetus to remove acid
to be attributable to masking of this effect by the increase in from the active tissues as soon as it is produced, and this is
catecholamines seen in acidotic states.3,4 achieved through three main mechanisms whose effect varies
The body uses alterations in pH to its advantage, as in timescale:
demonstrated by the function of the haemoglobineoxygen (i) Neutralisation via buffer systems (seconds to minutes)
dissociation curve. Haemoglobin is constructed of 4 haem (ii) Exhalation by the respiratory system (minutes to hours)
units (2a, 2b). There is a degree of flexibility in how they are (iii) Clearance by the renal system (hours to days)
joined, and the spatial arrangement alters the availability of
the binding points for oxygen. There are two conformations, a
relaxed (R) high O2 affinity form and a taut (T) low affinity
form. An increase in [Hþ] causes protonation of the N-termi-
Buffer systems
nal amino group of the a-subunit and the C-terminal histidine A buffer is a system that resists a change in pH. It consists of a
of the b-subunit, thereby stabilising the T form and reducing solution of a weak acid and its conjugate base. Although
the oxygen affinity of haemoglobin sot that the dissociation buffers do not actually add or remove acid, they act to
curve moves to the right. This is the Bohr effect. neutralise the harmful effects of an increased [Hþ] whilst
The O2 content of blood (CaO2) can be quantified as other mechanisms act.

100
90
80
70
60
Sa2

50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20
Pa2 (kPa)
pH 7.4 pH 7.2 pH 7.0

Fig 1 Alteration in oxygen carriage by haemoglobin with varying pH.4 Reproduced with permission.

BJA Education - Volume 22, Number 10, 2022 397

Acidebase balance

Hþ þ Ae # HA H2CO3 ! HCO3e þ Hþ

There is an equilibrium that is established between the The pKa of this reaction is 6.1, the pH at which the ratio of
ionised and non-ionised forms that can be defined by the rate HCOe 3 to H2CO3 is 1:1. This is the pH at which the system has
constant K. the greatest ability to resist a change caused by additional acid
or base. From the buffer titration curve, we see that this is well
½Hþ½A below the physiological pH; at pH 7.4 the ratio of HCOe 3 to
Ka ¼ H2CO3 is 5000:1.5 Theoretically this is at the weakest point for
½HA
the buffer lying on the flat part of the sigmoid curve (Fig. 2).
We can rearrange this as: The bicarbonate system is important for two reasons.
Firstly, it is the most plentiful buffer within the body; sec-
½HA ondly, it acts as an open buffer system. The classical buffer
½Hþ  ¼ Ka ðHenderson equationÞ
½A  describes a closed system, the acid and its conjugate base are
dependent only on each other, unaffected by other reactions.
Taking logarithms:
However, the bicarbonate buffer acts as part of an open
equilibrium. The respiratory system is able to remove CO2
pH ¼ pKa from the body, adjusting the equilibrium towards carbonic
½HA acid removing an increased amount of Hþ.
þlog ðHenderson  Hasselbalch equationÞ
½A
CO2 þ H2O ! H2CO3 ! HCO3e þ Hþ
The addition of Hþ to a solution increases the rate of
bonding to Ae and forms HA. The pKa is the pH at which [Ae] ¼
Applying the HendersoneHasselbalch equation to the
[HA]. The power of a buffer is greatest when it is working at a
HCO3/H2CO3 system:
pH around its pKa. The buffering capacity of blood is depen-
dent on (i) the concentration of the buffer and (ii) the pH. The ½HCO3  ½HCO3 
buffering capacity of the body is normally approximately 75 pH ¼ pKa þ log or pH ¼ pKa þ log
½CO2  aPCO2
mmol L1 at pH 7.4.
Buffer systems occur throughout the body, both intracel- where a is the solubility of CO2 in blood; using Henry’s law
lular and extracellular (Table 1). [H2CO3] ¼ aPCO2.
The predominant acid produced is carbonic acid, a by- Consider a closed system scenario and the normal values
product of aerobic respiration in the breakdown of carbohy- 1 1
for [HCOe
3 ] (24 mmol L ) and [CO2] (1.2 mmol L ).
drates within the mitochondria.
24
pHð7:4Þ ¼ pKa ð6:1Þ þ log
C6H12O6 þ 6O2 0 6CO2 þ 6H2O with the production of ATP. 1:2
If there is an increase in CO2 of 1 mmol L1 this would
Although z10% of the CO2 is transported to the lungs
alter the [HCO3]/[CO2] ratio to 23/2.2 and the pH would change
dissolved in plasma, the majority is transported as either
to 7.2. A step of 2 mmol L1 would leave a [HCO3]/[CO2] ratio
HCOe3 (z60%) or carbamino compounds (z30%).
22/3.2 and the pH would move to 6.9.
Now consider an open system. Should there be a change of
2 mmol L1 in CO2 there would be a corresponding decrease in
ca the HCOe 3 . However, in reality there would be accommodation
CO2 þ H2O ! H2CO3 ! HCO3e þ Hþ
by the respiratory system and the extra CO2 would be exhaled
and return it to near 1.2 mmol L1; thus this would leave a
When CO2 combines with water it forms carbonic acid.
[HCOe 3 ]/[CO2] ratio at 22/1.2 and have a pH of 7.36.
This reaction is slow with an equilibration time of several
minutes, but this is reduced to a fraction of a second by the
catalytic enzyme carbonic anhydrase (ca). This enzyme, Carbamino compounds
although not present within plasma, is widespread
Carbamino compounds are produced by the combination of
throughout the body d in particular within red blood cells, the
CO2 with the terminal amine groups of proteins. This reaction
nephron and the gastrointestinal tract. Dissolved CO2 rapidly
occurs with both intracellular and extracellular proteins, the
moves into red blood cells and reacts with H2O producing
most significant one being haemoglobin. Both haemoglobin
carbonic acid, which because of its low pKa rapidly dissociates.
and oxyhaemoglobin can combine with CO2. Hbe is less acidic
The bicarbonate/carbonic acid system
than OxyHbe and is able to combine with more Hþ (3.5 times
greater affinity).6 This is the Haldane effect.

Table 1 Buffer systems in the body. Effect of acidebase control on respiration

Extracellular Intracellular Carbon dioxide is released and exhaled within the lungs. By
the law of mass action Hþ clearance matches that of CO2. The
Bicarbonate/carbonic Haemoglobin buffer (Hb,H/Hbe partial pressure of CO2 or Hþ concentration in the blood has an
acid buffer system and OxyHb,H/OxyHbe) indirect effect on the respiratory centre of the brainstem via
Plasma proteins Phosphate (H2PO4/HPO4e)
signals from the chemosensitive area of the ventral surface of
Intracellular proteins
the medulla. This lies within the bloodebrain barrier (BBB). Hþ
cannot cross the BBB under normal conditions, but CO2 can.

398 BJA Education - Volume 22, Number 10, 2022

 Acidebase balance

kPa increase PCO2. In contrast, the response to a change in the

normal range of pH 7.3e7.5 in only one tenth as great.5 Res-
0 100 piratory adaptation is a constant process, not just in disease.
form of H2CO3 and CO2
Percent of buffer in Normal

Percent of buffer in
Any metabolic activity such as exercise is associated with an
operating

form of HCO–3

Base added
25 75 increase in CO2 production and this increases ventilation.
point in body
Acid added

50 pK 50
Renal regulation of acidebase control
75 25 The kidneys are responsible for the excretion of non-volatile
acids. These are produced by the metabolism of amino
acids. A normal dietary intake of 70 g day1 produces 190
100 0
mmol acids: hydrochloric acid (HCl) from the breakdown of
4 5 6 7 8
arginine, lysine and histidine; sulphuric acid (H2SO4) from
pH methionine and cystine. Most of this acid is used in the
breakdown and recycling of organic anions (glutamate,
Fig 2 Titration buffer curve for the bicarbonate buffer system.5 Reproduced aspartate and lactate), and the remaining 40e80 mmol day1
with permission. must be excreted by the kidneys.
Quantitively, of more significance to the body is the reab-
sorption of HCOe 3 . Each day more than 4000 mmol are filtered
Paradoxically the effect of CO2 on respiration is probably into the glomerular lumen of which 80e90% is reabsorbed in the
caused by alterations in Hþ concentration. The buffering of proximal convoluted tubule (PCT). HCOe 3 is not readily reab-
the CSF is less than in the plasma, and so CO2 crossing the BBB sorbed across the cell membrane; however, the cells of the PCT
rapidly reacts with H2O to form Hþ and HCOe þ
3 . The H then excrete Hþ into the lumen (via a Naþ/Hþ cotransporter) where,
elicits the response from the chemosensitive area. under the action of a membrane bound carbonic anhydrase,
There is a steep linear respiratory response to an increase they react to form CO2 and H2O. CO2, driven down a concen-
in PCO2 throughout the normal physiological range (PCO2 4e13 tration gradient, readily crosses into the cell through aquaporins
kPa). Alveolar ventilation increases by 1e2 L min1 for each 0.1 where the reaction is reversed. Hþ is recycled into the lumen

Lumen PCT Cell Interstitial space

HCO3–
Na+

Na+ Na+
HCO3– + H+ H+ + HCO3– H2CO3
CA
CO2 + H2O
H2CO3
Blood
CA Aquaporin

H2O + CO2

ATPase 2K+

3Na+

Fig 3 Acidebase control in the proximal convoluted tubule.

BJA Education - Volume 22, Number 10, 2022 399

Acidebase balance

þ
whereas HCOe 3 is moved by a Na /HCO3 co-transporter into the
e
excreted in this way and accounts for 30e40 mEq of Hþ
interstitial fluid and returned to the blood (Fig. 3). excretion. The presence of the titratable acids in the filtrate,
The remaining HCO3 passes through the loop of Henle to binds free Hþ and maintains the concentration gradient for Hþ
the distal convoluted tubule (DCT) where most is reabsorbed. across the cellular membrane, enabling further HCOe 3 pro-
Here the cellular excretion of Hþ is driven by Hþ/Kþ-ATPase duction and transfer back into the body.
and an aldosterone dependent Naþ/Hþ exchange. Ammonium is responsible for the remaining non-volatile
The body is able to modify the pH of urine from pH 8 to pH acid clearance at ~40e50 mmol day1. NH3/NHþ 4 is not a use-
4.5. However, even at maximum acidification (0.003 mmol L1 ful buffer as its pKa ¼ 9.2 is too far away from physiological pH.
Hþ), only a small proportion of the Hþ can be cleared in its free Instead, there is a combined role of the kidney and liver.
form; the remaining is cleared fixed to the titratable acids Through the metabolism of amino acids in normal dietary
(phosphoric acid z 80%, uric acid z20% and citric acid) or to protein, approximately 7000e1000 mmol NHþ 4 are produced.
ammonium. About 95% of NHþ 4 is combined in equal amounts with HCO3 to
e

form urea and excreted in the urine, with no net acidebase

HPO42e þ Hþ ! H2PO4e effect. The activity of the urea cycle in the liver is dependent
on the amino acid load of the diet (Fig. 4).
NH3 þ Hþ ! NH4þ The proportion of NH4e not combined with HCO3e in the
formation of urea is used to affect the acidebase equilibrium.
Phosphate is filtered into the glomerular lumen; it is Free ammonium ions are toxic in high levels and so are
reabsorbed to a lesser extent than H2O in the PCT and be- combined with glutamate in the liver to form glutamine; this
comes concentrated. Tubular fluid tends to be acidic as absorbs one NHþ 4 ion without using a HCO3 .
e

phosphate, with a pKa ¼ 6.8, and takes on a more important Glutamine passes to the kidneys into the cells of the PCT;
buffer role than in the plasma. Once formed H2PO4 is excreted here it is cleaved first by mitochondrial glutaminase then by
as a sodium salt. Overall, 5e10% of the filtered phosphate is cytosol glutamate dehydrogenase to release 2 NHþ 4 and a-

NH4+ + Glutamate

Glutamine

Renal Tubule PCT cell Interstitial tissue

Glutamine
– NH4 –
NH4
NH4– + Glutamate
Na+ Na+

NH4– + D-Keto-Glutarate

H+
H+ H+ + NH3
Glucose Glucose
Na+ Na+
+
H + NH3

NH4–

Blood
Loop of Henle

Fig 4 Renal and hepatic cooperation in acidebase control. PCT, proximal convoluted tubule.

400 BJA Education - Volume 22, Number 10, 2022

 Acidebase balance

ketoglutarate; the latter is converted to glucose within the cell Declaration of interests
and returned to the body. Conversion to glucose requires one
The authors declare that they have no conflicts of interest.
Hþ so the net effect is 1 Hþ (as NHþ
4 ) per molecule of glutamine.
NHþ 4 is either moved into the tubular fluid co-transported
directly with Naþ or dissociates to NH3 and Hþ. NH3 can pass
through the cell membrane down a concentration gradient MCQs
and Hþ is co-transported with Naþ. The associated MCQs (to support CME/CPD activity) will be
Once in the tubular fluid, NH4þ is reformed and moved into accessible at www.bjaed.org/cme/home by subscribers to BJA
the loop of Henle  . In the interstitium there is significant Education.
reabsorption and concentration of NH4þ. This contributes to
the hyperosmolarity of the renal medulla. However, in the
collecting duct Hþ ions are actively pumped into the tubular
References
fluid and recombine with NH3, moving by passive diffusion, to
reform NHþ 4 and are thus removed from the body. 1. Severinghaus JW, Astrup P, Murray JF. Blood gas analysis
The consumption and clearance of NH4þ via either the urea and critical care medicine. Am J Respir Crit Care Med 1998;
cycle or the glutamate/glutamine system is controlled by 157: 114e22
feedback mechanisms affected by pH status. Within 1e2 days 2. Rhodes A, Evans L, Alhazzani W et al. Surviving Sepsis
of the development of a metabolic acidosis there is increased Campaign: international guidelines for management of
hepatic glutamine production (at the expense of urea pro- sepsis and septic shock: 2016. Crit Care Med 2017; 45:
duction) and renal glutaminase activity enabling a three-fold 486e552
increase in clearance of NH4. Thus, the liver has a direct ef- 3. Mitchell JH, Wilbenthal K, Johnson RL. The effects of acid-
fect on the acidebase status of the body. base disturbances on cardiovascular and pulmonary
function. Kidney Int 1972; 1: 376e89
4. Handy JM, Soni N. Physiological effects of hyperchloraemia
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