Hydrogen ion (pH) and gas behavior during deep hypothermic cardiopulmonary bypass: Physiology and clinical implications

Abstract

Deep hypothermic cardiopulmonary bypass (CPB) is used in selected procedures such as pulmonary endarterectomy (PEA) and aortic arch repair. Hypothermia induces metabolic and physicochemical changes that affect hydrogen ion concentration ([H⁺]), haemoglobin–dioxygen (O₂) binding, O₂ consumption, and carbon dioxide (CO₂) production. Modern blood gas analysers provide instantaneous measurements of blood pH, PO₂, and PCO₂, enabling rapid bedside assessment of acid–base disturbances. Accurate interpretation, however, requires an understanding of the underlying physical and chemical principles. Acid–base management during hypothermic CPB is typically guided by either a pH-stat (interpreting blood gases at the patient’s actual temperature) or an alpha-stat strategy (interpreting blood gases at 37°C, independently of the patient’s actual temperature). The optimal strategy remains debated. This review clarifies key physiological principles of acid–base regulation, the effects of temperature on blood pH and gas solubility, and their clinical implications, with the aim of supporting accurate interpretation of blood gas values during hypothermic CPB.

Keywords

hydrogen pH hypothermia deep hypothermic circulatory arrest dioxygen carbon dioxide alpha-stat pH-stat

Introduction

As intensive care clinicians and anaesthesiologists, we routinely work with scientific concepts drawn from physics, biochemistry, biology, and mathematics. Ventilator management and the assessment of blood oxygenation rely on fundamental physical principles, particularly gas laws. Likewise, interpreting acid–base disorders requires an understanding of key physicochemical concepts such as electroneutrality, conservation of mass and thermodynamics.¹ Since their introduction in the 1960s in intensive care units (ICUs) and subsequently in operating rooms (ORs), arterial blood gas (ABG) analysers have transformed the assessment of acid–base disorders and gas exchange by providing rapid bedside measurements of pH, PO₂, PCO₂, and derived variables.² This has enabled a more dynamic, physiology-based interpretation of acid–base disorders. However, it has also led to misunderstandings when complex biochemical processes are approached with overly reductionist interpretations. In adults, deep hypothermic cardiopulmonary bypass (CPB) is used for procedures requiring circulatory arrest, such as pulmonary endarterectomy (PEA) and aortic arch repair.³ Cerebral protection relies largely on metabolism slowing through temperature reduction, sometimes as low as 18°C.³ Yet deep hypothermia markedly alters acid–base status and gas solubility and affects several metabolic functions.^3,4 Two main strategies are used for acid–base/CO₂ management during hypothermia: (1) a pH-stat strategy, which interprets ABGs at the patient’s actual temperature; and (2) an alpha-stat strategy, which interprets ABGs at 37°C, independently of the patient’s actual temperature. Which approach yields better clinical outcomes remains contested.^5–8 Beyond this debate, our objective is to clarify the physiological concepts required for accurate interpretation of ABG values during hypothermic CPB.

General reminders about fundamental concepts

Basic physicochemical principles

An aqueous solution is neutral when the concentrations of hydrogen ([H⁺] or [H₃O⁺]) and hydroxyl ions ([OH^-]) are equal.¹ Neutral pH depends on system conditions such as temperature and pressure. For example, water has a neutral pH of 7.0 at 25°C, but not at 37°C.¹ Under physiological conditions, the extracellular fluid is alkaline ([OH^-] > [H⁺]), with a pH of about 7.4 at 37°C.¹ Intracellular fluid pH is closer to neutrality, typically ranging between 6.8 and 7.2 at 37°C, although values vary widely across cell types and even between different organelles.^9,10

Water dissociates into two ions, H⁺ and OH^-, but its dissociation constant is very low at 37°C; as a result, water behaves almost as a nonelectrolyte solution.¹ Its concentration in the human body is roughly 55 mol/L at 37°C, vastly exceeding the concentration of free H⁺, and thus serving as an inexhaustible reservoir of H⁺ (Figure 1).¹ Dissociation and reassociation of water occur rapidly; consequently, H⁺ does not diffuse freely, nor does it cross cellular membranes via specialized transporters. Instead, it is generated and consumed quasi-instantaneously within biochemical reactions.^1,10

Figure 1.

Determinants of [H⁺] and pH in human body fluids. pH is the negative decimal logarithm expression of hydrogen ion concentration. It is a dependent variable determined by three main factors: the strong ion difference (SID), the partial pressure of CO₂ ( $P_{CO 2}$ ) and the total concentration of weak acid. At 37°C and standard atmospheric pressure, [H⁺] = 4.0 × 10⁻⁸ mmol/l, corresponding to a pH of7.40. Strong electrolytes are substances that are completely dissociated in solution, whereas weak electrolytes are only partially dissociated in solution under given conditions of pressure, temperature and [H⁺]. At equilibrium, the rate of dissociation equals the rate of recombination. The degree of the dissociation depends on the physicochemical conditions applied to the system and, under specific conditions, a substance may become completely dissociated. Water can be considered a weak acid with a very small dissociation constant. The dissociation and reassociation reactions of water are extremely rapid in both directions, such that equilibrium is always reached in biological fluids. The dissociation constant is a thermodynamic parameter exponentially related to the standard free energy change of the reaction at constant pressure and temperature. K_w denotes the dissociation constant of water (at 37°C $K_{w}^{'} = K_{w} [H_{2} O] = 4.3 \times 10^{- 16}$ Eq/l). Sc represents the solubility coefficient of CO₂ in the body fluid considered; It depends on the physicochemical properties of the fluid and on temperature.

In biological fluids, pH (i.e., [H⁺]) is determined by three main factors: the strong ion difference (SID; the difference between strong cations and strong anions), the concentration of dissolved CO₂ (PCO₂ in an open CO₂ systems), and the total concentration of weak acids (A_tot) (Figure 1).¹ Quantitatively, SID is the most important determinant of pH.^1,10

The composition of intracellular and extracellular fluids is quite different. The intracellular space contains higher levels of potassium (K⁺) and magnesium ions, and relatively lower levels of sodium (Na⁺) and chloride (Cl⁻) ions.^1,10 The SID is higher in intracellular than in extracellular fluids because of the abundance of proteins. Molecule exchange between compartments is tightly controlled; only water and CO₂ diffuse freely across cell membranes.¹¹

Most metabolic reactions occur intracellularly and are highly dependent on pH, making intracellular pH the variable of interest.^9,10 Unfortunately, only plasma pH is available at bedside. Plasma and intracellular pH are related, but not interchangeable.^9,10,12

CO₂ metabolism

CO₂ and water are formed by the reduction of O₂; this process is aerobic cellular metabolism. CO₂ production is proportional to metabolic rate, and CO₂ clearance is regulated through ventilation.^1,9 CO₂ diffuses across the cellular membrane into the bloodstream, through which it is transported to the lungs for elimination. Once CO₂ is dissolved in blood, it undergoes a series of reversible reactions: hydration to carbonic acid (H₂CO₃), dissociation into H⁺ and bicarbonate (HCO₃^-), and further conversion into carbonate (CO₃²⁻). Because PCO₂ is in equilibrium with H₂CO₃, it is proportional to H₂CO₃. [HCO₃⁻] and [CO₃²⁻] depend on both PCO₂ and SID.^1,10 A small fraction of CO₂ can also bind to proteins, forming carbamino compounds.¹

Atmospheric PCO₂ remains relatively constant. Because the body functions as an open system for CO₂, it maintains the concentration of dissolved CO₂ in body fluids within a narrow range. Dissolved CO₂ in blood equilibrates with alveolar CO₂. Alveolar CO₂ can rapidly change through adjustments in alveolar ventilation in response to variations in CO₂ production—for example, during physical exertion. This dynamic regulation ensures that increases in CO₂ only transiently modify pH.^1,9

Dissolved CO₂ in body fluids, conveniently referred to as PCO₂, is an independent variable that determines pH. In a closed system, however, the total CO₂ content− including all forms of CO₂− becomes the independent variable. When CO₂ is added, it will cause a sustained modification in pH.^1,9

Blood is a tissue made up of red and white blood cells, platelets, and plasma. Haemoglobin in RBCs makes up most intracellular weak acids. The affinity of CO₂ for haemoglobin depends on several factors, including O₂, pH, temperature, 2,3 diphosphoglycerate (2,3 DPG) concentration, and diphosphoglycerate mutase activity.¹³

What occurs inside RBCs does not directly influence plasma pH because RBCs are impermeable to proteins like haemoglobin. Consequently, haemoglobin does not function as a buffer for plasma pH. Instead, RBCs can interact indirectly with plasma pH by modulating the SID through active exchange of strong ions such as Na⁺, K⁺, and Cl⁻ (Hamburger effect).^1,14

Temperature considerations

Temperature shifts the equilibrium of chemical reactions according to Le Chatelier’s principle and, in doing so, alters the pH of water-based solutions. From a thermodynamic standpoint, an increase in temperature favours endothermic reactions (reactions that consume heat), whereas a decrease in temperature favours exothermic reactions (reactions that release heat). Consequently, hypothermia slows water dissociation and decreases CO₂ production, which tends to raise pH.¹

Temperature also affects the function of macromolecules by altering their structure, three-dimensional conformation, and binding sites.¹⁵ Humans are homeothermic (endothermic) vertebrates, capable of maintaining a stable internal temperature through continuous heat production and tight thermoregulatory control.^15,16 However, body temperature varies slightly with circadian rhythm and is not uniformly distributed across body regions.¹⁷ There are also inter-individual variations related to factors such as body surface area, adipose tissue content, and environmental conditions.¹⁸

During hypothermic CPB, the targeted degree of hypothermia may be mild, moderate, deep, or even profound. In the present review, we used the following classification: Mild hypothermia corresponds to temperatures ranging between 28.1–34°C; moderate hypothermia to temperatures ranging between 20.1°–28°C; deep hypothermia for temperatures ranging between 14.1–20°C; and profound hypothermia for temperatures below 14°C.¹⁹

Partial pressure of a gas

According to Dalton’s law, the partial pressure of a gas is defined as the pressure that the gas would exert if it were the only gas occupying the volume considered. According to Henry’s law, the concentration of an ideal gas dissolved in a liquid is proportional to its partial pressure in the gas phase above the liquid, if temperature and pressure remain constant. This is a thermodynamic process: the partial pressure of a gas reflects the kinetic energy (or molecular agitation) of its particles, corresponding to the frequency of their collision with the walls of the gas container. As temperature increases, molecular kinetic energy increases, and the partial pressure of the gas rises accordingly. The amount of gas dissolved in a liquid depends not only on its partial pressure but also on the physicochemical properties of the liquid and on ambient temperature and pressure.

Blood gas analysers measure PO₂, PCO₂ and pH using a dedicated electrochemical or optical technology. PO₂ is assessed either with a Clark polarographic electrode or an optical sensor.^20,21 In the Clark electrode, O₂ molecules, diffuse from the blood towards a platinum cathode, where they undergo reduction. This reaction generates an electric current which is directly proportional to the concentrations of dissolved O₂ and therefore reflects PO₂. Optical sensors, in contrast, rely on luminescence-based properties: specific dyes emit photons when excited, and the presence of O₂ quenches this fluorescence.²¹ The degree of fluorescence quenching enables a direct measure of dissolved O₂ concentrations.²¹

PCO₂ is measured using a pH-sensitive electrode. CO₂ diffusing into the measurement chamber undergoes hydration to H₂CO₃, which dissociates into HCO₃^- and H⁺. The resulting change in pH is proportional to the PCO₂ of the blood sample.

All measurements are performed at 37°C inside the analyser. A temperature-correction algorithm is then applied to calculate values adjusted to the patient’s actual temperature, yielding the reported ¨temperature-corrected¨ blood gas results.

Finally…

The alpha-stat hypothesis refers to a conceptual framework describing how pH, PCO₂, and total CO₂ content vary with temperature. First proposed by Reeves in 1972, it states that pH changes with temperature in a manner that preserves a constant ratio between the deprotonated and protonated forms of imidazole groups on histidine residues within proteins.^22,23 In other terms, the temperature-induced variation in pH parallels the temperature-dependent change in the negative logarithm of the dissociation constant (pK_a) of the histidyl–imidazole group.^22,23 Maintaining this constant imidazole dissociation ratio preserves the net charge of proteins, thereby supporting optimal enzymatic activity and stabilizing the three-dimensional (functional) conformation of proteins.^22,23

Effect of temperature on blood pH

Temperature dynamically modifies extracellular pH in both ectotherms (cold-blooded) and endotherms (warm-blooded) vertebrates. In their pioneering work, Austin et al. observed in alligators an arterial pH variation (dpH/ΔT) of −0.0018 pH unit per °C.²⁴ Ectotherms often use the alpha-stat regulation to maintain their physiological state. However, not all ectotherms follow this pattern; for instance, the black racer snake (Coluber constrictor) maintains a constant arterial pH despite temperature changes.²⁵

In contrast, hibernating mammals adopt a pH-stat regulation during torpor, maintaining a relatively constant pH despite decreased metabolic demands and body temperature. As a result, they develop hypercapnia and acidosis.²⁶ Interestingly, some hibernating mammals shift to alpha-stat regulation during arousal.²⁶

In non-hibernating mammals, the situation is more complex. Thermoregulatory mechanisms usually maintain a stable internal temperature, limiting the natural expression of alpha-stat behaviour. However, when these mechanisms are overridden or blunted—such as during anaesthesia—alpha-stat regulation may be predominant.^26,27 In alpha-stat organisms, pH increases by approximately 0.0015–0.0018 units for each 1°C decrease in temperature.^22,23,28,29 Physiological studies have shown that isolated human blood and dog blood follow alpha-stat behaviour during hypothermia: at a constant total CO₂ content, PCO₂ decreases while pH increases.^30,31

Through its effect on water dissociation, CO₂ production and elimination and the SID, temperature dynamically alter pH. The total amount of non-volatile weak acid (A_tot), another determinant of pH, can reasonably be considered stable across temperature changes.

A rise in temperature drives the water dissociation forward, increasing [H⁺] and lowering pH. Conversely, hypothermia reduces molecular kinetic energy, shifts the reaction backwards, lowers [H⁺], and increases pH (Figure 2).

Figure 2.

Effect of hypothermia on [H⁺] and dissolved gases. Hypothermia affects the pH of water-based solutions through several mechanisms. First, it shifts the water dissociation equilibrium towards reduced dissociation, leading to a decrease in [H⁺] and an increase in pH. Second, hypothermia slows cellular metabolism, thereby reducing CO₂ production. In addition, hypothermia decreases molecular kinetic energy, which increases the solubility of gases. In blood, this leads to increased concentrations of dissolved O₂ and CO₂ despite lower corresponding partial pressures. Hypothermia also shifts the oxyhaemoglobin dissociation curve to the left, reflected by a decrease in P50 (the arterial PO₂ at which 50% of haemoglobin is saturated), indicating increased haemoglobin affinity for O₂.

Temperature also affects metabolism, and thus CO₂ production.³² It is important to note that the metabolic response to cold varies across species, among mammals, and according to the level of exposure. In unanaesthetised mammals, the initial response to cold exposure is an increase in heat production to counteract heat loss. Consequently, O₂ consumption (VO₂) rises, and alveolar ventilation and/or O₂ extraction increases accordingly.^26,27

From this point onward, the term hypothermia refers to a fall in core temperature beyond the body’s thermoregulatory capacity, as occurs in anaesthetised patients undergoing hypothermic CPB.

Hypothermia slows metabolism and CO₂ production.^32,33 The human body normally behaves as an open system for CO₂.^1,10 PCO₂ is determined by ventilation, whereas total body CO₂ content remains relatively constant.^1,10 The concentrations of CO₂ in its other forms (HCO₃⁻, CO₃²⁻, H₂CO₃) depend primarily on SID, while PCO₂ is determined solely by cellular production and ventilation.^1,10

Hypothermia alters pulmonary mechanics by reducing lung compliance and depressing O₂ and CO₂ chemoreceptor function.^26,34 In unanaesthetised, non-hibernating mammals experiencing hypothermia, alveolar ventilation −and consequently CO₂ elimination − decline in parallel with VO₂, and through the direct depressant effect of hypothermia on ventilation.^34–36

However, in mechanically ventilated subjects or during CPB, ventilation is controlled by the clinician or the perfusionist; the body is therefore no longer a “fully” open CO₂ system. Hypothermia markedly increases the solubility of CO₂ and decreases plasma buffering capacity. An identical change in alveolar ventilation produces a larger pH shift in hypothermia than in normothermia.^14,37 As a result, minute ventilation or sweep gas flow must be carefully adjusted at each temperature step according to the targeted PCO₂ (alpha or pH-stat strategy).

Hypothermia also induces mineral and metabolic changes that can modify SID, and therefore, pH. For example, lactate may accumulate due to shivering, or tissue hypoxia.¹⁴ Additionally, hypothermia enhances renal Na⁺ excretion and impairs tubular transport, limiting the kidney’s ability to regulate acid-base balance.^14,38

Effect of temperature on dissolved gas in blood

To better understand the effect of temperature on O₂ and CO₂ concentrations in blood, it is helpful to first consider how an ideal gas behaves when dissolved in a liquid. Let us take the example of O₂ dissolved in water at atmospheric pressure and constant temperature (T₀). Over time, the system reaches equilibrium, where the rate at which gas molecules enter the liquid equals the rate at which they leave. At this point, the relationship between the different variables is described by Henry’s law:

(1) {C (T)}_{gas} = \frac{1}{k_{H}} \times {P (T)}_{gas}

Where

{C (T)}_{gas}

is the concentration of the gas in the liquid,

{P (T)}_{gas}

is the partial pressure of the gas in the gas phase,

k_{H}

is (the improperly named) Henry’s law constant, which depends on the physicochemical properties of the gas-liquid system as well as on temperature and pressure. If the temperature of the system is increased from T₀ to T₁ (with T₁>T₀), the kinetic energy of dissolved molecules increases, making O₂ molecules more likely to leave the liquid phase. After a new equilibrium is reached, the concentration of dissolved O₂ is therefore lower. This illustrates a key concept: the solubility of a gas in a liquid varies inversely with temperature −the colder the liquid, the greater its capacity to dissolve gas. It’s important to remember that Henry’s law describes ideal gas behaviour under constant pressure and temperature, conditions that rarely, if ever, occur in vivo. In fact, gases like O₂ and CO₂ in blood are not ideal:

CO₂ undergoes hydration and dissociation (forming H₂CO₃, HCO3⁻, CO₃²⁻) and binds to proteins and haemoglobin. O₂ binds extensively to haemoglobin and is continually consumed in mitochondria.

Furthermore, Henry’s law applies only when true thermodynamic equilibrium is reached. In contrast, in living organisms, dissolved gases are continuously added and removed through alveolar ventilation, cardiac output, tissue perfusion, and metabolic demands (VO₂ and CO₂ production). Consequently, equilibrium is never truly achieved in vivo, and Henry’s law provides only a partial approximation of gas behaviour in blood.

We can now consider the effect of temperature on blood gases such as O₂ and CO₂. Hypothermia decreases CO₂ production and increases CO₂ solubility, which lowers arterial PCO₂. It also decreases VO₂, increases O₂ solubility, and shifts the oxyhaemoglobin dissociation curve (ODC) to the left. Clinically, these effects on O₂ are highly relevant: during deep hypothermia, because O₂ becomes more soluble and therefore more available in its dissolved form, a substantial proportion of metabolic demand can be met by dissolved O₂ alone.^5,39–42

During hypothermia, acid–base management can be achieved using either the pH-stat or alpha-stat strategy, each leading to very different pH and PCO₂ values.^8,37 However, a fundamental subtlety is often overlooked when discussing dissolved gases in blood: outside the lungs, blood has no interface with a gas phase.¹ The lungs are the only organ where blood gases reach equilibrium with an actual gas phase—in the alveoli—after diffusing across a thin cellular and extracellular barrier.¹ In healthy subjects, end-tidal PCO₂ is approximately equal to arterial PCO₂; however, the corresponding concentration of dissolved CO₂ depends not only on the solubility coefficient of CO₂, but also on the extent of its chemical interactions with plasma, RBCs, water, and proteins. For convenience, we routinely express the amount of dissolved gas in terms of partial pressure.¹ However, this is a conceptual abstraction − an indirect and simplified representation of molecular concentrations in blood. It does not fully reflect the underlying physiology and has no literal gas-phase analogue in the bloodstream.¹ This raises an important question: does this conceptual gap matter in clinical practice?

Partial pressure or concentration: why does it matter?

PO₂ and PCO₂ are widely used to assess pulmonary gas exchange and blood oxygenation. Blood gas analysers report O₂ and CO₂ as partial pressures, which do not represent direct measurements of total gas content but rather reflect the gaseous tension of O₂ and CO₂ dissolved in plasma, as they equilibrate with the alveolar gas. As such, these values are primarily meaningful for evaluating the efficiency of gas exchange between blood and lungs. Nevertheless, PO₂ and PCO₂ are frequently interpreted as surrogates for gas concentrations in blood, which can lead to oversimplifications and misunderstandings of physiological and metabolic processes. There are two main reasons for this:

First, under normobaric conditions, the chemical and biological effects of a substance in a living organism are governed by its molar concentration (i.e., the number of molecules per unit volume), or by its activity in the case of ionized molecules.¹ For example, carotid bodies sense blood O₂ concentration—not PO₂—through specific chemoreceptors (hence the term chemoreceptor rather than baroreceptor). Aortic bodies also respond primarily to changes in O₂ content rather than PO₂.^43,44 Likewise, mitochondria act as intracellular O₂ sensors and trigger the transcription of hypoxia-inducible factor (HIF) in response to changes in O₂ concentration.⁴⁵ Second, in living organisms, the partial pressure of a gas does not reflect its molar concentration in a linear manner because O₂ and CO₂ do not behave as ideal gases. Both gases interact chemically with blood compounds. Dissolved CO₂ concentration depends not only on CO₂ production, but also on temperature, pH, and ventilation. As a result, the quantity of dissolved CO₂ varies continuously and dynamically, and true equilibrium—as described by Henry’s law—is never achieved in vivo. Hypothermia provides a clear example of this limitation: for a given total CO₂ content, hypothermia increases dissolved CO₂ while decreasing PCO₂. This illustrates why PCO₂ cannot reliably serve as a surrogate for dissolved CO₂ or its metabolic effects (table 1).³¹

Table 1.

Arterial blood gas during deep hypothermia.

	Corrected to temperature (18°C- pH stat)	Uncorrected to temperature (37°C-alpha stat)
pH	7.51	7,30
$P_{CO 2}$ (mmHg)	22.2	42.7
$P_{O 2}$ (mmHg)	546	682
S_aO₂ (%)	100	100
O₂ Solubility coefficient (ml of O₂/ml of blood/mmHg)	0.00392	0.00302
[O₂ dissolved] (ml of O₂/ml of blood)	2,14	2.06

Table 1 shows the results of an arterial blood gas analysis performed at 18°C in a patient undergoing pulmonary endarterectomy and highlights the marked differences between temperature-corrected and uncorrected partial pressure values. Blood gas analysers warm the sample to 37°C, resulting in an apparent increase in partial pressure in the gas phase. However, in terms of concentration, the number of O₂ molecules per unit volume remains unchanged regardless of temperature. Changes in temperature do not generate additional O₂ molecules; they only modify O₂ solubility and the position of the oxyhaemoglobin dissociation curve. At the very high values observed in this example, haemoglobin binding sites are fully saturated, even after rewarming. Because O₂ solubility increases with hypothermia, the concentration of dissolved O₂ is higher at 18°C than at 37°C.

Hypothermia also reduces CO₂ production and increases its solubility, while simultaneously altering the equilibria of CO₂-related reactions - in water-based solutions. As a result, the concentration of dissolved CO₂ cannot be reliably inferred from the partial pressure reported by the temperature-corrected blood gas values.

The behaviour of O₂ is somewhat simpler because it interacts predominantly with haemoglobin. When haemoglobin is fully saturated, O₂ approximates ideal gas behaviour, and dissolved O₂ is approximately proportional to PO₂. However, even for O₂, this relationship breaks down under altered physiological conditions, such as hypothermia, where dissolved O₂ concentration increases while PO₂ decreases.

In conclusion, metabolic processes are driven by the molecular concentration of dissolved gases rather than their partial pressures. Partial pressures are useful surrogates for evaluating pulmonary gas exchange, but only under conditions in which Henry’s law applies.

Temperature, solubility, and gas formation

If a gas is dissolved in a liquid under constant pressure and temperature, the liquid can hold only a finite maximal amount of that gas; this state is referred to as saturation. When the amount of dissolved gas exceeds this limit, the system is oversaturated. In oversaturated liquids, dissolved gas may undergo a phase transition and form bubbles as it separates from the liquid phase. This phenomenon is central to the pathophysiology of decompression sickness, which affects divers and individuals exposed to hyperbaric environments.⁴⁶ To illustrate the mechanism, consider a diver breathing compressed air. During descent, ambient pressure increases by one bar for every 10 meters of seawater, increasing the partial pressures of inhaled gases—particularly nitrogen (N₂). This promotes diffusion of N₂ into blood and tissues down its concentration gradient.⁴⁶ Tissue N₂ content rises with depth and duration of exposure. If ascent is too rapid, ambient pressure falls faster than N₂ can be eliminated via the lungs, causing PN₂ in blood and tissues to transiently exceed ambient pressure. This oversaturation favours bubble formation and may lead to decompression sickness.⁴⁶

Fortunately, at the surface—under normobaric conditions (atmospheric pressure ≈ 101.3 kPa, 1 bar, or 760 mmHg, with body temperature around 37°C)—blood cannot become oversaturated with N₂ or O₂, even when breathing 100% O₂. Two factors explain this. First, arterial PO₂ is always lower than alveolar PO₂, which itself is necessarily below atmospheric pressure because of water vapour pressure. Second, O₂ is continuously consumed by cells, preventing accumulation in blood and tissues, in contrast to N₂, which is biologically inert and not metabolised.

During deep hypothermic CPB, the situation differs. Changes in blood temperature can promote endogenous bubble formation, particularly during two critical phases: cooling—when cold blood exiting the oxygenator mixes with warmer aortic blood—and rewarming.⁴⁷ As discussed above, hypothermia increases gas solubility in blood. Depending on the inspired O₂ fraction (F_iO₂) and the duration of hypothermia, blood may accumulate high dissolved quantities of N₂ and/or O₂. During subsequent rewarming, rising temperature reduces gas solubility, allowing dissolved gases to undergo a phase transition and form microbubbles. These gas emboli may contribute to postoperative neurological injury.

Several studies have examined gas emboli during hypothermic CPB to define safer cooling and rewarming strategies. In a pioneering study, Donald et al. reported that gaseous microemboli are released during both cooling and rewarming, and recommended minimising temperature gradients between CPB arterial outflow and venous inflow.⁴⁷ Animal studies subsequently confirmed endogenous microemboli formation when temperature gradients between blood and the heat exchanger reached values as high as 10°C.^48,49 More recent investigations have suggested that up to 63 mL of gas may be released during the rewarming phase alone.⁵⁰ Accordingly, guidelines emphasise maintaining a temperature gradient of less than 10–12°C between the blood and the heat exchanger. In addition, it is recommended to keep the arterial–venous blood temperature gradient below 10°C when blood temperature is below 30°C, and below 4°C when blood temperature exceeds 30°C.^47,51

Key points and clinical implications

Interpreting blood gas variables during hypothermic CPB is challenging. The following physiological concepts help structure clinical reasoning and avoid common misconceptions.

(1) Patients under deep sedation, mechanical ventilation, and CPB are unable to mount physiological adaptive ventilatory responses to acute changes in temperature and [H₊], because they are no longer a fully “open” system for CO₂ exchange. Extracellular—and intracellular—pH is therefore significantly influenced by temperature, through both changes in water dissociation and the associated decrease in CO₂ production. Correction of pH can be achieved by adjusting ventilation or CPB sweep gas flow, modifying SID, or directly adding CO₂ to the CPB circuit.

(2) Temperature-corrected PO₂ and PCO₂ values have limited relevance for understanding gas diffusion between blood and cells. Instead, CO₂ and O₂ should be considered in terms of molar or volumetric concentrations (i.e., the number of gas molecules or volume per volume of blood). According to physical laws, hypothermia increases the solubility of both O₂ and CO₂ in blood. Consequently, for a given O₂ and CO₂ content, the concentrations of dissolved O₂ and CO₂ increase, resulting in lower PO₂ and PCO₂ values in the hypothetical gas phase surrounding the blood.^52,53

It must be emphasized that temperature-corrected blood gas values are not directly measured but calculated, and that no standardized reference ranges exist for PO₂ or PCO₂ at temperatures other than 37°C. Furthermore, O₂ and CO₂ do not strictly obey Henry’s law because of their chemical interactions with water and blood components. As a result, estimating gas concentrations from partial pressure is unreliable, except for O₂ when haemoglobin is fully saturated.

(3) Markers such as oxygen delivery (DO₂), veno-arterial O₂ difference, and VO₂ are useful for assessing tissue oxygenation during CPB. Deep hypothermia markedly increases haemoglobin affinity for O₂, limiting O₂ release to tissues. Several studies suggest that, during deep hypothermic CPB, tissue oxygenation may rely predominantly on dissolved O₂ rather than haemoglobin-bound O₂.^5,39–42

Accordingly, increasing F_iO₂ during cooling may increase dissolved O₂ availability and help reduce the risk of tissue hypoxia, particularly during periods of circulatory arrest. This approach may also limit endogenous microemboli formation by reducing tissue N₂ accumulation.⁴²

Caution is warranted when interpreting venous O₂ saturation (SvO₂) during hypothermic CPB. High SvO₂ values are expected because of increased O₂ solubility and the leftward shift of the ODC. Thus, SvO₂ does not reliably reflect the balance between O₂ supply and metabolic demand and should not be used as a surrogate marker of adequate tissue oxygenation in this context.^41,42

Classic biological markers such as serum lactate remain useful indicators of impaired O₂ utilisation; however, they must be interpreted cautiously. Hypoxia—defined as reduced mitochondrial O₂ availability—may occur in the absence of hyperlactatemia.^54,55 Conversely, hyperlactatemia may reflect mechanisms unrelated to tissue hypoxia, such as reduced hepatic lactate clearance or increased production due to shivering.^14,56

Urine output, although often used to assess the adequacy of blood flow relative to metabolic demand, is a poor marker of metabolic adequacy during deep hypothermic CPB. CPB can impair renal function through multiple mechanisms, including hypoperfusion, non-pulsatile flow, systemic inflammation, haemolysis, and inadequate venous drainage. The effects of moderate and deep hypothermia on tubular function remain poorly understood.^14,57 Glomerular filtration rate is tightly coupled to systemic blood flow and typically decreases during cooling.¹⁴

However, polyuria with dilute urine is frequently observed during cooling. The mechanism is unclear but may involve sympathetic nervous system activation and hypothermia-induced tubular dysfunction.^14,58 Therefore, current evidence is insufficient to support urine output as a reliable indicator of renal function or metabolic demand during deep hypothermic CPB.

(4) Most proteins are intracellular, where intracellular pH is tightly regulated.^9,59 CO₂ diffuses readily across cellular membranes.¹ Consequently, during pH-stat management, changes in extracellular CO₂ will also influence intracellular pH. The addition of CO₂ to the blood should therefore be considered carefully, as the resulting increase in dissolved CO₂ concentration may be difficult to predict. CO₂ also crosses the blood–brain barrier and can decrease cerebral intracellular pH, leading to cerebral vasodilatation. Some authors argue that this may be beneficial during hypothermic CPB by improving cerebral blood flow and cooling, whereas others suggest it could increase the risk of cerebral oedema or exacerbate reperfusion injury.^37,60

(5) The controversy regarding the optimal pH management strategy remains unresolved. Both strategies have potential benefits and drawbacks, and clinical studies have yielded inconsistent results (Figure 3).^5,60–63

Figure 3.

Advantages and limitations of alpha-stat and pH-stat strategies. Figure 3 depicts the potential advantages and risks associated with the pH-stat and alpha-stat strategies with respect to cerebral blood flow and metabolism (Image(s) provided by Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Potential benefits of pH-stat management include several mechanisms. First, it leverages the vasodilatory effect of CO₂ on the cerebral vasculature, which increases cerebral blood flow and may enhance brain cooling.^9,31 Second, intracellular acidosis can inhibit cellular metabolism, thereby reducing VO₂. Third, the extracellular decrease in pH promotes O₂ release from haemoglobin (Bohr effect).^60,64,65 Fourth, at the cellular level, pH-stat management decreases intracellular pH and may activate protective pathways, including improved mitochondrial stability and enhanced antioxidant defences.^31,66,67 However, the metabolic inhibition associated with pH-stat management may become clinically relevant only after a certain duration, which can exceed the length of many surgical procedures.^9,32,60 Moreover, pH-stat management has been associated with cerebral hyperperfusion (“luxury perfusion”), which may increase the risk of cerebral microembolisation.⁶⁰

Experimental and clinical studies have yielded divergent results depending on patient population and depth of hypothermia. Animal studies have shown that pH-stat management increases cerebral blood flow, improves brain cooling, and improves oxygenation—through the Bohr effect—and has been associated with better preservation of cerebral metabolism.^7,68–70 These findings have also been reported in infants undergoing deep hypothermic circulatory arrest.⁵ In contrast, in adults undergoing moderate hypothermic CPB (approximately 26°C), alpha-stat management has been associated with superior neurological outcomes compared with pH-stat management.^60–62

From an evolutionary and physiological perspective, alpha-stat regulation may better preserve cerebral metabolic coupling, cellular homeostasis, and enzymatic structure and function in endothermic vertebrates.^9,22,32 Importantly, there is no obligation to apply a single acid–base management strategy throughout the entire procedure. Several authors have proposed a hybrid approach tailored to surgical phases and guided by cerebral monitoring tools such as near-infrared spectroscopy (NIRS) or transcranial Doppler.^9,53,71 For example, some suggest using a pH-stat strategy during cooling and up to circulatory arrest, then transitioning to alpha-stat management before circulatory arrest or during rewarming.^53,71

(6) During deep hypothermic CPB, numerous factors other than temperature can influence acid–base status. These include the nature and volume of administered fluids, the degree of haemodilution, the adequacy of pump-delivered blood flow relative to metabolic demand, changes in blood viscosity and microcirculatory perfusion, and renal dysfunction secondary to systemic inflammation, haemolysis, or inadequate perfusion. Each of these variables can independently or synergistically alter metabolic and acid–base balance and should be considered when interpreting blood gas and metabolic variables during hypothermic CPB.

Conclusion

Acid–base and oxygenation management during hypothermic CPB are complex and clinically high-stakes. Hypothermia profoundly alters water dissociation, CO₂ production, and gas solubility, which disrupts the usual relationship between partial pressure and dissolved gas concentration. Clinically, this means that temperature-corrected blood gas values should not be interpreted in isolation; management should be guided by physiological targets (e.g., pH strategy, CO₂ handling, oxygen content and delivery) and by the surgical phase. Practically, clinicians must anticipate stepwise changes in pH and PCO₂ with cooling and rewarming and actively adjust ventilation or CPB sweep gas flow, SID, and—when appropriate—F_iO₂ to maintain adequate O₂delivery, which during deep hypothermia may depend largely on dissolved O₂. In parallel, limiting temperature gradients during cooling and rewarming is essential to mitigate endogenous microbubble formation and its neurological consequences. The optimal acid–base strategy remains controversial, with no definitive consensus on whether alpha-stat or pH-stat management is superior; a phase-adapted, individualised hybrid approach guided by cerebral and metabolic monitoring (e.g., NIRS, transcranial Doppler, DO₂/VO₂, lactate trends) is likely to be the most clinically pragmatic and physiologically coherent option.

Take home message

In biological solutions, hypothermia slows water dissociation and reduces CO₂ production, resulting in an increase in pH.

- Hypothermia increases gas solubility. For a given O₂ and CO₂ content, the concentrations of dissolved O₂ and CO₂ increase, while PO₂ and PCO₂ decrease.

- Temperature-corrected PO₂ and PCO₂ values have limited relevance for understanding gas diffusion between blood and cells. CO₂ and O₂ must be considered in terms of their respective concentrations.

- The pH-stat strategy lowers intracellular pH because CO₂ freely crosses cell membranes. Its effects on cerebral perfusion are difficult to predict and therefore require close monitoring.

- The choice between alpha-stat or pH-stat strategies remains controversial, and there is no obligation to apply a single strategy throughout the procedure. A hybrid approach, tailored to surgical phases and guided by cerebral monitoring, may be the most appropriate.

Footnotes

Acknowledgement

We want to thank all the members of our perfusion team, for their work and day to day commitment.

ORCID iD

Sylvain Diop

Author contributions

SD and RM wrote the first draft of the manuscript. JT and MCK reviewed it critically and made substantial corrections. All authors approved the final version of the manuscript.

Funding

Financial/Non-financial disclosure: Support was provided solely from institutional and/or departmental sources.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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