Influence Of Variations In Systemic Blood Flow Biology Essay

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Cerebral autoregulation can be defined in terms of static and dynamic autoregulation. The static approach, illustrated by the classical autoregulation curve model, contains a collection of regulatory mechanisms that maintain constant cerebral blood flow (CBF) during changes in cerebral perfusion pressure (CPP). Dynamic autoregulation comprises cerebrovascular resistance changes or simply arteriolar caliber changes as blood pressure or perfusion pressure varies, suggesting a predominantly CPP-mediated system to maintain the normal chemical milieu of the brain.

Assumed as an important factor that influences CBF, the phenomenon blood pressure roughly consists of two components: cardiac output (CO) and total peripheral resistance (TPR). These components are inextricably linked through the aortic-carotid baroreflex system. Therefore, we aim to investigate whether alterations in systemic blood flow or alterations in MAP, by a clamped output, have the greatest effect on CBF.

Methods: In 11 patients undergoing elective cardiac surgery, cerebral oxygenation was measured by near infrared spectroscopy (NIRS). During cardio pulmonary bypass (CPB) a number of interventions was implemented. Pump flow rate and mean arterial blood pressure (MAP) were altered to five conditions: (1) increase in MAP using phenylephrine; (2) increase in MAP using vasopressin; (3) decrease in MAP using sodium nitroprusside; (4) reduction in flow rate by 0.5 l/min/m2; and (5) increase in flow rate by 0.5 l/min/m2. These interventions were executed randomly.

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Results: Pharmacologically induced increase in MAP by a clamped cardiac output showed a decrease in cerebral oxygenation. Phenylephrine demonstrated a reduction of xx% (±SD%) (p=…), where vasopressin showed a significant reduction with xx% (±SD%) (p=…). A decrease in MAP induced by sodium nitroprusside showed a stable cerebral oxygenation. Alterations in flow rate demonstrated significant changes in rSO2. Increased blood flow caused an increase in rSO2 by xx% (±SD%) (p=….) and decreased blood flow showed an decrease in rSO2 by xx% (±SD%) (p=….).

Conclusion: These results demonstrate that systemic blood flow is an important factor in maintaining CBF, supporting the growing evidence of the influence of cardiac output on CBF. Furthermore a pharmacologically induced increase in MAP by a clamped cardiac output showed a decrease in CBF, postulating a new insight for the rationale of perioperative management of the hypotensive patient.

Introduction

Cerebral autoregulation

Traditionally, cerebral autoregulation is defined as a collection of regulatory mechanisms that maintain constant cerebral blood flow (CBF) during changes in cerebral perfusion pressure (CPP, usually expressed as mean arterial blood pressure minus intracranial pressure).(2;3) Like this, CBF remains relatively constant within the mean arterial blood pressure (MAP) limits of 50 to about 150 mm Hg. This steady-state or static approach is the basis for the classical autoregulation curve model (figure 1).

Figure

The classical cerebral autoregulation curve proposed by N. Lassen.(1) Each data point is the averaged pre-test steady state value of a study. Note that CBF remains constant while mean arterial pressure increases.

Independently of the basic mechanism, changes in perfusion pressure lead to vasomotor adjustments in cerebral vascular resistance (CVR) thus following CBF to stay relatively constant. The limits of cerebral autoregulation reflect the points at witch vasomotor adjustments are exhausted and CVR cannot either increase or decrease further to regulate CBF. Outside these limits CBF tends to follow changes in CPP and therefore perfusion pressure-flow autoregulation is lost.(5)

Alternatively, cerebral autoregulation can be defined in terms of cerebrovascular resistance changes or simply arteriolar calibre changes as blood pressure or perfusion pressure varies.(6) In this view cerebral autoregulation is a more dynamic concept and predominantly a CPP-mediated system. Apparently, the cerebral perfusion is regulated in such a way as to maintain scrupulously the normal chemical milieu of the brain. This suggests the influence of a regulatory mechanism governed by the metabolic demands of the cerebral tissues.(1)

This distinction between static and dynamic autoregulation shows diverse aspects of the complex phenomenon of cerebral autoregulation. In accordance with this, cerebral autoregulation can be evaluated by static methods or by dynamic methods. Although static and dynamic testing may asses some different aspects of the cerebral response to changes in MAP, static and dynamic tests of cerebral autoregulation yield similar results.(7)

Assumed as an important factor that influences CBF, the phenomenon blood pressure can roughly be divided into two components: cardiac output (CO) and total peripheral resistance (TPR). The aortic-carotid baroreflex systems respond to momentary changes in systolic blood pressure, adjusting the degree of peripheral vasoconstriction and cardiac output to allow maintenance of a relatively constant perfusion pressure.(8) Consequently TPR and CO are inextricably linked. This leads to the query whether there is a relationship between CO and CBF. Well, a growing number of clinical studies suggest a significant influence of cardiac output on CBF.(9-11) This means that when blood pressure alters, CO directly alters with that. However we do not know whether the change in CBF due to an increase in blood pressure is a consequence of the change in blood pressure or the change in CO. Therefore, our study investigated the effect of alterations in blood pressure by a clamped cardiac output and the effect of alterations in blood pressure induced by changes in blood flow on cerebral oxygenation, representing cerebral autoregulation.

Hypothesis and Aim

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To explore the effect of changes in (MAP) and changes in systemic blood flow most accurately, we need to vary these two parameters separately during mild hypothermic (≥ 33°C) cardio pulmonary bypass (CPB). Systemic blood pressure can be varied with the administration of vasoactive substances. Systemic blood flow can only be varied manually when a patient is on CPB. Therefore we choose to perform this study on patients who undergo cardiac surgery.

Hypothesis

We hypothesize that as we vary MAP separately from blood flow, we find a compensatory mechanism, meaning there is no effect on the cerebral saturation. In contrast, when we vary blood flow and thus MAP, we expect a significant effect on the cerebral oxygenation.

Aim

The aim of this study is to investigate whether alterations in systemic flow or alterations in MAP, by a clamped output, have the greatest effect on cerebral oxygenation.

Material and methods

Study design

This clinical study has a cross-over design. In all subjects, the response to variations of the flow and the blood pressure was investigated. The order of variations was assigned randomly and the number of interventions was executed as many as possible depending on the hemodynamics and pumping-time of the subject concerned.

Study period

In this report the amount of patients described were enrolled over a period of seventeen weeks, starting in March 2010. Since measurements only take place intra-operatively and there is no follow-up, the duration of the whole study is dependent on the number of suitable patients being operated.

Study population

Our study group was patients on cardiopulmonary bypass. Patients were eligible when they were scheduled for elective coronary bypass grafting (CABG), aortic valve repair or replacement, mitral valve repair or replacement, either combinations of the former.

Inclusion criteria were:

- Age 18-70 years

- Patients scheduled for elective cardiac surgery (CABG, aortic or mitral valve implantation, or combinations of the former), using mild hypothermic cardiopulmonary bypass

- Written informed consent

Additional exclusion criteria were:

- Brain pathology in history (CVA)

- Severe carotid artery stenosis

- Severe COPD

- Diabetes mellitus

- Kidney failure

Assessment of cerebral autoregulation

A 'golden standard' for the assessment of cerebral autoregulation is not available, moreover there is a considerable disparity in methods and criteria. Also, different tests asses different aspects of autoregulation. This is comprehensible because cerebral autoregulation is essentially a concept rather than a physically measurable entity.(5;12) As such, the methods to be employed and the interpretation of results will be necessarily dependent on the models adopted to conceptualize the phenomenon of autoregulation. The distinction between a static and a dynamic autoregulation is a clear example of different approaches arising from different models of autoregulation. The challenge to find appropriate methods to 'measure' or asses cerebral autoregulation is made more difficult by the many physiological variables that can influence CBF.(5) Weglaten?

In this study we approach cerebral autoregulation as a dynamic concept and on that account we assume that cerebral autoregulation is focused on maintaining homeostasis of the cerebral metabolic rate (CMR) of oxygen (CMRO2).(1) For this reason we choose to monitor cerebral autoregulation through near-infrared spectroscopy (NIRS). NIRS is a technique that has been unrolled since virtually four decennia and can be used as a noninvasive and continuous monitor of the balance between cerebral oxygen delivery and consumption. The NIRS technology is based on the principle that each tissue substance has a distinctive light absorbance.(13) A light emitting diode (LED) send specific near infrared light wavelengths through the brain tissue, which are then returned to a light detector a few centimetres apart.(14) As there is a relationship between the depth of tissue penetration and the angle of incidence of the reflected light, there are two detectors at different distance from the LED. This facilitates the use of a subtraction algorithm to distinguish the extracerebral from the intracerebral signal, thus providing a measure of cortical oxygenation.(13) Changes in the detected intensity of near infrared light reflect the changes in oxyhemoglobin (cO2Hb) or deoxyhemoglobin (cHb) concentration, then the ratio between these two is measured and consequently corrected for the superficial signal to obtain the regional oxygen saturation (rSO2) of the cortex.(13;14)

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For NIRS monitoring we choose to use a quite novel device, the Nonin® Model 7600

regional oximeter with 8000CA sensor utilizes Equanoxâ„¢. This technique incorporates two light emitting diodes with three-wavelength and two detecting photo diodes to determine cerebral hemoglobin oxygen saturation (figure 2). Dual emitter sites eliminate surface variability by having the LEDs illuminate alternately at 730nm, 810nm and 880nm wavelengths for enhanced precision.(4)

Figure 2

The EQUANOX technology: dual emitters alternately create pairs of reflected light paths through surface tissue to the shallow receiver and through the cerebral cortex to the far receiver. The system algorithm first uses the dual emitter architecture to remove surface effects that modulate light amplitude and then uses the shallow path to remove the surface tissue components from the deep path signals - resulting in a cerebral cortex measurement that is unaffected by intervening tissue or surface effects.(4)

On arrival at the operating room, a sensor of the Nonin® device was positioned on one side of the forehead. This enables the monitoring of regional cerebral oxygenation in the watershed areas of the middle and anterior cerebral artery. The side of the sensor was determined randomly. The sensor was placed according to the manufacturers instructions with the patient resting quietly. Baseline rSO2 values were obtained and stored. After application of routine monitoring in the operation room, including ECG, radial and pulmonary artery catheters with beat to beat measurement of hemodynamics (Nexfin Beat-to-Beat Cardiovascular Monitor), patients were anesthetized with 0.05-0.15 mg/kg midazolam and 0.15-0,30 mg/kg etomidate or 1.5-2.5 mg/kg propofol. Analgesia was induced with 2 μg/kg sufentanil. Muscle relaxation was achieved with 1 mg/kg rocuronium and the trachea was intubated. After induction of anesthesia nasapharyngeal and rectal temperature probes and a urinary catheter were placed. Anesthetic management of clinical variables including heart rate, arterial blood pressure, ventilation, systemic oxygen saturation, temperature, depth of anesthesia, and related variables were done according to good clinical practice and the choice of the anesthesiologist who was responsible at the time of measurements. Transesophageal echocardiography was routinely performed by the anaesthesiologist in all patients.

After sternotomy, the aorta ascendens and the right atrium were cannulated. CPB was conducted using an artificial lung with integrated venous/cardiotomy filter reservoir primed with colloids and crystalloids and in-line monitoring of venous saturation and hematocrit. All aspired cardiotomy blood was filtered and returned to the patient directly.

During cardiac surgery, the patient is usually cooled down. Since cerebral autoregulation is lost at body temperatures lower than 33 degrees centigrade, all our interventions were performed with body temperatures greater than 33 degrees.(15-18)

Medication

During the measurements, patients were anaesthetized with propofol and sufentanil. This drug does not compromise cerebral autoregulation in clinical used dosages.(19;20) Phenylephrine, used to raise systemic blood pressure, is a sympathomimetic, alfa-adrenergic receptor agonist with little beta-adrenergic receptor effect. This drug is used in daily practice to regulate blood pressure intraoperatively. To raise blood pressure we used a bolus of 50-100 μg. Sodiumnitroprusside is also used in daily practice. It lowers blood pressure through the release of NO from endothelial cells, thus reducing peripheral resistance. To decrease blood pressure we used a bolus of 25-50 μg. In our hospital vasopressin is not generally in use, but is a widely accepted vasoactive agent. Vasopressin binds to V1 receptors on vascular smooth muscle cells to cause direct vasoconstriction without inotropic and chronotropic effects. To increase blood pressure we used a bolus of 0.2-0.4 units.

Interventions

When the patient was on CPB, we modified the systemic blood pressure or systemic blood flow while measuring the cerebral oxygenation. We performed measurements during which the systemic blood pressure was modified, and measurements during which the systemic flow was modified. Before each intervention, we recorded a baseline for one minute. During this baseline recording, no modifications were made. When the baseline value was obtained, we implemented one of the interventions named below. This process was repeated for as many interventions as possible, depending on the hemodynamics and pumping-time of the patient concerned.

Figure 3

During surgery MAP was maintained in the range 70 - 90 mmHg. With our interventions, we induced a raise and a reduction in blood pressure about 15 mmHg. This is within the normal range during operations. Systemic flow was regulated by the CPB-operator. Normally CPB-flow is maintained at circa 2.6 l/min/m2. With our interventions, we raised and reduced this with 0.5 l/min/m2. This is also within the normal range.

Modifications in blood pressure:

Increase of the systemic blood pressure about 15 mmHg, using

phenylephrine

Increase of the systemic blood pressure about 15 mmHg, using

vasopressin

Reduction of the systemic blood pressure about 15 mmHg, using

sodiumnitroprusside

Modifications in blood flow:

Reduction of the blood flow by 0.5 l/min/m2

Increase of the blood flow by 0.5 l/min/m2

These interventions were implemented randomly.

Statistics

All data entries were made directly into a Case Report Form (CRF). Individual sets of Case Report Forms were used for each patient. The data obtained from the Nonin® device and the Nexfin Beat-to-Beat Cardiovascular Monitor have variable sampling rates. Nexfin software was used to equidistantly resample the data by polynomial interpolation with a frequency of 0,008 Hz. These data were inserted into one database for each individual patient and another database collecting the specific data for each intervention. Data were presented in graphs. In this way, the temporal effect of our interventions is best pointed out. Statistical significance was determined using repeated measurements ANOVA. Post hoc analysis was performed using a Tuckey's test.

Ethics

Approval of the medical ethical committee of the Academic Medical Centre Amsterdam was obtained. Before participation in the study procedure written informed consent has to be signed. The investigated interventions are within the physiological range of variations. No adverse effects of changes of the hemodynamics within the proposed limits are known. Anesthesia and surgical technique will be applied according to standard procedures.

Results

Table 1 Patient characteristics

 

 

N

 

10

 

Sex

 

 

 

Female, n (%)

4

40%

 

Male, n (%)

6

60%

Mean age, yrs (range)

 

 

Female, yrs (range)

 

 

Male, yrs (range)

 

 

Mean weight, kg (range)

 

 

Mean height, cm (range)

 

 

Surgery

 

 

 

CABG

0

 

 

MAVR

1

 

 

Bio-AVR

2

 

 

MVP

 

 

MVR

 

 

Combination

7

 

Interventions

 

 

Phenylephrine not on CPB

5

 

 

Phenylephrine during CPB

10

 

 

Vasopressin

7

 

 

CPB-flow up (0,5 l/m²)

9

 

 

CPB-flow down (0,5 l/m²)

8

 

 

Sodiumnitroprusside

10

 

Riskfactors

???????

 

 

Hypertension

5

 

XXX patients scheduled for elective cardiac surgery with use of CPB were included. Patient characteristic are presented in table 1. Subjects were informed of the study procedures and possible risks involved in the study, and written informed consent was obtained. One patient was excluded because the nasopharyngeal temperature was below 33 degrees centigrade and thus interventions could not be implemented.

Tabel klopt nu kwa getallen nog niet

Phenylephrine

The intervention with phenylephrine was implemented in 10 patients (6 men, 2 women; mean age 61.9 (range 51-69) years; weight????;height???; nodig??? à of toevoegen aan patient characteristics?

Baseline MAP was xx ± SD mmHg. The administration of phenylephrine led to an increase in MAP of xx ± SD mmHg. The increase in MAP due to administration of phenylephrine while cardiac output was clamped showed a decrease in rSO2 with x% (P=……).(figure XX)

Vasopressine

In XX patients (xxxxx) the intervention with vasopressin was carried out. Baseline MAP was xx ± SD mmHg. The administration of vasopressin led to an increase in MAP of xx ± SD mmHg. The increase in MAP due to administration of vasopressin while cardiac output was clamped showed a decrease in rSO2 with x% (P=……).(figure XX)

CPB-flow up

In XX patients (xxxx) CPB-flow was increased with 0,5 l/m2. Baseline MAP was xx ± SD mmHg. The increase in CPB-flow caused a rise in MAP of xx ± SD mmHg. The increase in MAP due to increased CPB-flow showed an increase in rSO2 with x% (P=……).(figure XX)

CPB-flow down

In XX patients (xxxx) CPB-flow was decreased with 0,5 l/m2. Baseline MAP was xx ± SD mmHg. The decrease in CPB-flow caused a diminishment in MAP of xx ± SD mmHg. The decrease in MAP due to decreased CPB-flow showed a decrease in rSO2 with x% (P=……).(figure XX)

Sodium nitroprusside

The intervention with sodiumnitroprusside was implemented in XX patients (xxx). Baseline MAP was xx ± SD mmHg. The administration of sodium nitroprusside led to a decrease in MAP of xx ± SD mmHg. The decrease in MAP due to administration of sodium nitroprusside while cardiac output was clamped showed stable rSO2/a decrease in rSO2 with x% (P=……).(figure XX)

Discussion

The present study monitored the effect of changes in blood pressure on cerebral oxygenation in patients with a clamped cardiac output. We have shown that a pharmacological (both phenylephrine and vasopressin) mediated increase in MAP showed a decrease in cerebral oxygenation, where a pharmacologically mediated decrease in MAP did not show a significant alteration in rSO2. Prompt increase or decrease in/of CPB/pump-flow by 0.5 l/m2 demonstrated a significant rise or fall in rSO2, respectively. These results suggest that systemic blood flow is an important component that contributes to CBF, whereas vasoconstrictive agents tend to increase the total peripheral resistance in such a way that they decrease CBF.

- Hier al vergelijken met studie Lieshout+Secher over phenyl bij intact hart of later in de discussie na de considerations?

Considerations

Before we discuss the implications of our findings, several aspects require attention.

Critical for the interpretation of our data is the assessment of cerebral autoregulation. We used cerebral oximetry by near infrared spectroscopy. Although this method is increasingly used in cardiac surgery, this monitoring modality is still being discussed controversially. Davies et al.(21) doubt the usefulness of NIRS measurements as cerebral monitoring during cardiac surgery. Their main points of comment involve the regional nature, the high intersubject variability, and the unclear contribution of nonbrain sources. However Olsen et al.(22) found a significant relationship between CBF and rSO2, meaning that NIRS can be used as a method to evaluate changes in CBF. Our NIRS measurements were unilateral. While bilateral monitoring is recommended, evidence supporting that bilateral monitoring is beneficial over unilateral monitoring is scarce. Unilateral monitoring seems to be adequate as significant alterations in cerebral oxygenation will be parallel on both sides.(23)

Voorafmetingen om te laten zien dat CA intact is??? + Geinduceerde MAP verandering groot genoeg??? (ref. RI24 bij Niek)

In all patients induction of anesthesia was similar. Maintenance of anesthesia was performed according good clinical practice of the anaesthesiologist responsible during the surgical procedure. There are many pharmacological agents who influence cerebral autoregulation significantly. Some anesthetic agents affect or impair cerebral autoregulation. Volatile anesthetic agents have an intrinsic dose-dependent cerebral vasodilatory effect.(12) High-dose volatile anesthetic agents have cerebral vasodilating properties. Adversely, most intravenous anesthetics have vasoconstrictive capabilities. This assumption is affirmed by the fact that a commonly used anesthetic dose of 200 μg/kg/min propofol intravenous preserved cerebral autoregulation. The difference in vasomotor tone might clarify the impaired autoregulation during high-dose volatile anesthesia.(20) In accordance to this, maintenance of anesthesia during measurements on CPB was with propofol. Analgesia during surgery was done with sufentanil/fentanyl? Analgesics may, in some extent, compromise cerebral autoregulation, but all opioids maintain cerebral autoregulation, but reduce CBF in high doses.(19) Thus the drugs used for induction and maintenance of anesthesia during measurements are very unlikely to affect any aspect of cerebral autoregulation.

Our study protocol contains the vasoactive agents phenylephrine, vasopressin and sodium nitroprusside to induce changes in blood pressure. Administration of the alpha-adrenergic phenylephrine shows a decrease in rSO2, suggesting the influence of sympathetic activity in the brain. Whether sympathetic activity influences CBF and cerebral oxygenation remains debated. Stimulation of sympathetic activity by the administration of phenylephrine decreased cerebral oxygenation in healthy subject, but exercise of increasing intensity abolished the extent of these changes in regional cerebral oxygenation, possibly as a result of an increase in CMRO2. This suggests that cerebral oxygenation is influenced by sympathetic activity but that this influence is attenuated or lost as CMRO2 increases. The lack of an effect of phenylephrine on rSO2 during increased CMRO2 can be interpreted as supporting a balance between cerebral metabolism and a sympathetic restraint on blood flow. A restraint in cerebral oxygenation by phenylephrine could be established directly through a pharmacological effect or a reflex increase in cerebral vascular resistance triggered by the elevation in arterial pressure, eventually supported by a lowered cardiac output.(24) Cardiac output is reduced as a consequence of the aortic-carotid baroreflex systems who respond to a (sympathetically) mediated vasoconstriction with a reflex bradycardia and thus reducing cardiac output.(8;11;24)

To contradict the idea of sympathetic influences in the brain, vasopressin, which binds to V1 receptors, shows a similar decrease in rSO2 in our study. In addition, both human and animal studies indicate that phenylephrine has no relevant vasoconstriction of cerebral vasculature.(25;26)

Direct observations made during craniotomy have revealed that sodium nitroprusside does not affect the vessel diameter of the MCA.(27) These results are in accordance with our findings concerning that no alterations in rSO2 were observed by a decrease in blood pressure caused by administration of sodium nitroprusside. Vasoconstriction and vasodilatation, however, could depend on different mechanisms of action, which could vary individually. Even if the underlying mechanism was the same, it could be hypothesized that the abilities to dilate or constrict the cerebral arterioles may show some normal variability within individuals.(7) This all suggests that a pharmacologically induced rise in blood pressure with a clamped cardiac output and the concomitant decrease in rSO2 is due to an autoregulatory mechanism.

Doseringen niet gelijk/bloeddrukstijginen niet gelijk/hoog genoeg?….nog iets over zeggen?

Increasingly cardiac output is suggested as an important factor that might influence CBF independent of cerebral autoregulation. In healthy volunteers, a linear relationship between the changes in CBF and cardiac output has been found that was independent of cerebral autoregulation.(10) Changes in cardiac index and central venous pressure caused by tilting the heart during off-pump coronary artery bypass grafting provoked a decrease in rSO2.(28) In patients with congestive heart failure CBF was substantially reduced. After heart transplantation, CBF recovered in these patients.(9) In our study changes in pump-flow were followed by changes in rSO2. These findings are in line with the concept that systemic blood flow, either induced naturally by cardiac output or manually by CPB, influences CBF. Thus when cardiac output alters, CBF alters with it. Te heftige conclusie? Te dubbelop?

Cerebral autoregulation is not a static entity; it can be influenced by various stimuli including physiological stimuli (e.g. brain temperature),(3;17;18;29-32) biochemical stimuli (e.g. pH), metabolic substances (e.g. CO2).(33) It seems well known that CO2, as the main product of cerebral metabolism, is a powerful cerebral vasodilator and that simultaneous changes of pH play a secondary role or no role at all. These facts, combined with the local site of action of CO2, form the principal for a widely accepted theory concerning the physiological role of CO2.(1) So far meaning that hypocapnia (leading to an increase in vascular tone) enhances dynamic CA, whereas hypercapnia (causing a decrease in vascular tone) reduces autoregulatory response (figure XX).(2) Teveel over CO2?

Figure XX.

Relation between end-expiratory carbon dioxide partial pressure pCO2 and rate of regulation (RoR) in 10 healthy subject, made by Aaslid et al.(2) Observations in each subject (â-ª) are connected by lines. Dotted line was determined by regression analysis of all data (y=0.621-0.011 x; r=-0.717, p<0.001). â-¡, averages of all individual responses in each pCO2 state.

Regarding the metabolic demands of the brain, whole-body oxygen delivery can be mathematically matched to systemic oxygen requirement, nevertheless organs or tissues may differ in their ability to regulate their flow. Although total systemic oxygen delivery may be adequate during CPB, the distribution of that blood flow is not known. (17) Moderate variations in oxygen tensions around the normal level do not affect the cerebral blood flow. Although extreme oxygen tensions below and above the normal level appear to achieve an effect that is in the opposite direction to that of CO2.(1)

Because of these metabolic and biochemical influences on CBF, it is very important to maintain a constant internal milieu. Hence during CPB blood gas management was done by alpha-stat to maintain a normal pH (brain), preserve intracellular electrochemical neutrality, and improve the efficiency of intracellular enzymatic function.(3)

Several studies about cerebral autoregulation during CPB emphasize on the effect of body temperature on CBF. As far as the influence of CPB on cerebral autoregulation is concerned, Preisman et al.(16) showed that autoregulatory mechanisms remain preserved after mild hypothermic CPB. Newman et al.(30) concluded that cerebral autoregulation is slightly impaired during normothermic CPB. However, they only assessed CBF once in 15 minutes, compromising the reliability of their measurements. The brain temperature is an important determinant of cerebral blood flow during CPB.(3) In infants and children cerebral pressure-flow velocity autoregulation is preserved during normothermic CPB, begins to be altered at nasopharyngeal temperatures less than 25°C, and is lost at temperatures less than 20°C. In conjunction with other studies, this indicates that cerebral autoregulation is lost at temperatures between 23 and 25°C.(18) In addition to these findings, Van Bel et al.(32) suggested that there might be a lack of cerebral autoregulation during hypothermic CPB in neonates and infants, and Sungurtekin et al.(17) and Mutch et al.(29) showed that the autoregulation curve is not flat on both hypothermic and normothermic CPB.

Cerebral metabolism decreases exponentially with reduction in temperature. These changes in cerebral metabolism are associated with parallel changes in CBF. This "flow-metabolism coupling" is component of the dynamic concept of cerebral autoregulation. Because hypothermia reduces CMRO2 and autoregulation of CBF typically is coupled to metabolism, hypothermia also reduces CBF. Hypothermia reduces CBF linearly and CMRO2 exponentially. Accordingly, the ratio of CBF/CMRO2 increases with decreasing temperatures, so that at moderate hypothermia the ratio of CBF/CMRO2 is increased. This results in luxuriant brain flow.(3) To avoid any interference of brain temperature on cerebral autoregulation, interventions were not implemented when nasopharyngeal temperature was under 33 °C.

Routinely hemodilution is used during CPB. As a consequence, Hb concentration will drop. The influence of Hb concentration on cerebral oxygen supply is undisputed. Hence, decreased values of rSO2 might be a result of a lowered Hb concentration.(28) Observations of the whole surgical procedures, the phase of attachment of the patient to CPB showed a remarkable decrease in rSO2, which stabilizes as soon as the CPB was spinning on full flow. During the procedure Hb concentration was carefully monitored and therefore no blunt changes in Hb concentration were noticed. Moreover, our measurements regarded a few minutes each and observe a possible sudden alteration from one minute baseline induced by one of the implemented interventions. Thus the global variations in Hb concentration in the course of the whole surgical procedure are of no importance for our measurements.

Aging is associated with a decline in resting cerebral metabolism and CBF.(34) Lipsitz et al.(35) found that despite a reduction in CO2 responsiveness, elderly subjects retain cerebral autoregulatory capacity in response to acute orthostatic hypotension. Since the effect of aging on cerebral autoregulation remains to be fully elucidated, patients in our study were all under 70 years of age.

Our study group was patients on CPB, and thus cardiac patients. Cardiac patients often suffer from cardiovascular risk factors such as hypertension. Chronic hypertension shifts the lower and upper blood pressure limits of CBF autoregulation towards higher pressure. With chronic antihypertensive treatment, CBF autoregulation may re-adapt towards normal.(36) Although hypertension may affect cerebral autoregulation, despite it we did include patients with hypertension if they where on antihypertensive treatment.

Furthermore, in patients with generalized vessel pathology, like for example patients who suffer from type 2 diabetes mellitus, cerebral autoregulation is not intact. CBF and brain metabolism will in this case become dependent of blood pressure.(37) Because of this patients suffering from diabetes mellitus were not included.

Cerebral autoregulation is impaired with acute stroke. Immink et al.(38) found that in large middle cerebral artery territory stroke (MCAS) dynamic autoregulation was impaired in the affected hemisphere only. In lacunar ischemic stroke cerebral autoregulation was impaired bilaterally. In a follow-up study of patients experiencing minor MCAS, cerebral autoregulation was still abnormal on the affected side, but preserved on the normal side more than two months after stroke onset.(39) Since there is no certainty if there is any long term recovery of cerebral autoregulation, we did not include patients with stroke in history.

Clinical implications

The knowledge about the effect of certain hemodynamic variations on cerebral autoregulation may have an impact on various aspects of perioperative management of patients. A few studies on cerebral autoregulation during CPB focus on the effect of changes in MAP and pump flow rate on CBF in animals. Michler et al.(15) cooled baboons to 28°C and then varied the CPB pump flow rate and MAP to four conditions: full flow and low flow rates with average and low MAP induced pharmacologically. Sungurtekin et al. (17) also carried out four conditions varying pump flow rate and MAP in dogs on CPB. No pharmacological agents were used to decrease the blood pressure. Both authors concluded that when MAP is preserved, changes in pump flow rate do not alter CBF, thus meaning that CBF is independent of flow rate.

These findings are in contrast with our results. Possible declaration for this purpose is first of all the study subjects. Beside it, they assume that CBF and oxygen delivery are indirectly dependent on pump flow insomuch that the flow generates the MAP. Although MAP and pump flow are physiologically coupled over a broad range, they suggest that a relative primacy of MAP for CBF under conditions in which flow and pressure are dissociated.(17) On the other side, our data suggest that systemic blood flow is a more important component than MAP by itself that contributes to CBF. Because with a continuous pump flow a decrease in MAP does not show an alteration in rSO2, where an increase of MAP does show a decrease in rSO2. Changes in MAP elicited by altered pump flow did alter rSO2 with it, suggesting that systemic blood flow surpasses MAP.

In conclusion, the present investigation demonstrated that systemic blood flow is an important factor in maintaining CBF. These results support the growing evidence of the influence of cardiac output on CBF. Furthermore a pharmacologically induced increase in MAP by a clamped cardiac output showed a decrease in CBF, postulating a new insight for the rationale of perioperative management of the hypotensive patient. Moet ik hier nog precies uitleggen wat ik daarmee bedoel: dat ze niet denken dat ze het brein ermee beter maken…

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