What Blood Pressure is Appropriate for Cardiopulmonary Bypass and How To Get It

In 1995, Gold et al. published the results of a randomized clinical trial of elective coronary artery bypass grafting in 248 patients randomized to two groups (1). In one group, mean arterial pressure was maintained between 50 and 60 mmHg during cardiopulmonary bypass and in the other it was maintained between 80 and 100 mmHg. The incidence of combined cardiac and neurological complications was significantly lower in the high pressure group (4.8%) than in the low pressure group (12.9%: p = 0.026). Six months postoperatively, the mortality rates were 1.6% and 4%, stroke rates 2.4% and 7.2%, and cardiac complication rates 2.4% and 4.8%. Cognitive and functional status outcomes did not differ between the groups. This study precipitated a change in practice in our unit, more in response to casual discussion than in any formalised way. The use of vasoconstrictors to maintain higher mean arterial pressures has become the norm.

Gold’s study was cirticised when published on a number of grounds, notably the unjustifiable technique of selectively pooling data to achieve statistical significance. Other criticisms included the lack of data on the prevalence of post bypass and postoperative hypotension or hypertension.

WHAT IS THE TRUTH OF THE MATTER?

The primary reason for worrying about blood pressure on CPB is the potential for injury to the brain. Adverse cerebral outcomes after cardiac surgery are associated with higher in-hospital mortality, longer hospitalisation, and a higher rate of discharge to other facilities for further care (2). Factors which have the potential to affect neurocognitive outcomes after cardiac surgery include:

1. hypoperfusion (3,4,5)

2. cerebral embolic load (6)

3. hypoglycaemia (6)

4. hypertension (7)

5. atheromatous disease (8)

6. therapeutic agents (9)

7. temperature (10)

Studies of pressure during CPB need to take each of these into account. This has not always been the case. Stockard established the concept of tm⁵⁰ (the integral of perfusion pressure ≤50 mmHg over time) (11). We have the opportunity to study this in our own patients.

Cerebral perfusion pressure is the difference between mean arterial pressure and central venous pressure. The argument around perfusion pressure and cerebral blood flow is complicated. Low flow may be associated with hypoperfusion. High flow may increase embolic load. Brown has demonstrated a relationship between embolic load and bypass time (12) which links to other work showing poorer neurological outcomes with increased bypass times. Schmidt has demonstrated that cardiopulmonary bypass is associated with a significantly higher rate of cerebral injury in patients who were hypertensive preoperatively (7). Technical matters are also important (13)—including the design of equipment used during CPB (14,15). Putting the patient head down at critical moments in the procedure may reduce embolisation to the brain (16). Reducing the haematocrit may improve flow but the lowest haematocrit during CPB is an independent risk factor for mortality (risk is increased if the haematocrit ≤ 14%) (17). Transient hypertension during cardiac surgery has been associated with stroke. High perfusion pressure may be associated with more damage to blood elements and thereby exacerbate the inflammatory response to CPB. It may also compromise the surgical field.

Table 1.

Some factors which affect cerebral blood flow.

	Item
1	PaCO2
2	PaO2
3	Blood viscosity
4	Intercranial pressure
5	Mean arterial pressures
6	Central venous pressure
7	Drugs

The notion that 50 mmHg is a safe lower limit for MAP on CPB appears to reflect the notion that this is the lower limit at which autoregulation of the cerebral circulation occurs. Within the limits of autoregulation, flow is driven by cerebral metabolic rate rather than perfusion pressure. Cerebral metabolic rate is influenced (amongst other things) by hypothermia. In reality, the range of cerebral autoregulation varies between individuals, and studies show enormous between-patient variability in blood flows at any given pressure. The concept of a lower range of 50 mmHg seems to have been predicated on one or two older studies which have been subject to serious methodological criticism.

Acid base management is integral to any discussion of perfusion on bypass. pH is defined as the negative logarithm of the Hydrogen ion concentration ([H+]), or pH = ?log [H+]. Electrochemical neutrality is defined as the point where [H+] = [OH−]:

• Neutral pH (pN) is 7.00 at 25°C where [H⁺] = [OH⁻]=1×10⁻⁷ mole/L.

• For water, At 37°C pN is 6.80; at 17°C pN is 7.14.

• At 37°C intra-cellular pN is 6.80 and extra-cellular pN is 7.4 (the pN of blood).

During cooling of aqueous solutions, both [H⁺] and [OH⁻] decrease because the spontaneous dissociation of water decreases. Homeotherms maintain their temperature despite changes in their environment. Poikilotherms’ temperature changes with changes in the environmental temperature. Most poikilotherms tend to maintain intracellular pH near pN over a wide range of temperatures. As they cool, intra- and extra-cellular pH increases and so does pN (much as for water).

The constituent of proteins thought responsible for the remarkably constant intra-cellular balance between [H⁺] and [OH⁻]as temperature varies is histidine. The degree of dissociation of the imidazole group of histidine (approximately 0.55—called “α”) doesn’t change appreciably with temperature; instead, the pKa of the imidazole does vary. Humans appear to maintain α-stat physiology. This includes keeping the CO₂ content of the blood constant with varying temperature, because a change in CO₂ content would alter α.

Henry’s law states that the amount of gas in a solution is proportional to its partial pressure; as temperature drops, the partial pressure of CO₂ decreases, but its solubility increases, so the total content of CO₂ remains constant and so does α.

The object in α-stat management of CPB is to keep pH at 7.4 and pCO₂ at 40 mmHg as measured at 37°C. If the same samples were corrected to the patient’s temperature, these results would indicate a respiratory alkalosis (pH high, pCO₂ low). pH-stat involves aiming for the same targets after correction for temperature; this requires the addition of pCO₂ and is a more acidic technique. Most enzyme reactions have pH optima that follow the predictions of α-stat theory. Therefore metabolic rate would be expected to reduce with pH-Stat, and this is thought to be the mechanism by which hibernating species conserve oxygen (they follow pH-stat acid base physiology). However, in a study by Murkin discussed below (18), cerebral metabolic rate did not vary between pH-stat and α-stat management, so the former approach produced more flow for a given metabolic rate (see below). Other studies have shown lower metabolic rates with pH-stat, but at the temperatures typically used for adult CPB, the weight of current evidence suggests that there is very little difference in metabolic rate between the two approaches.

The relationship between cerebral blood flow and perfusion pressure depends on whether α-stat or pH-stat management of acid base is used. Murkin et al. has demonstrated that cerebral blood flow autoregulation is better maintained in presence of α-stat management (18). For most given cerebral perfusion pressures, cerebral blood flow is higher with pH-stat management of CPB (which may be a good or a bad thing—see above). At some temperatures this relationship reverses.

Bashein et al. showed that at moderate hypothermia, carbon dioxide management during cardiopulmonary bypass has no clinically significant effect on either neurobehavioural or cardiac outcome (19). In a study by Stephan and co-workers, new neurological deficits were more common in pH-stat patients. In a study by Patel and co-workers, the conclusion was “patients receiving alpha-stat management had less disruption of cerebral autoregulation during cardiopulmonary bypass, accompanied by a reduced incidence of postoperative cerebral dysfunction.” (20). This clinical advantage was consistent with findings in another study by Murkin (21).

How then should one control blood pressure on CPB? Dilators and constrictors seem to be more popular than alterations in flow rate, however we have a very poor understanding of the regional effects of these drugs. Given the forgoing discussion, it seems that the outcome of changing pressure by these manipulations is even less certain.