The effect of ketanserin on cerebral blood flow and cerebrovascular CO2 reactivity in healthy volunteers

Summary The effect of the anti-hypertensive agent ketanserin on the cerebral blood flow (CBF) and the cerebrovascular CO₂ reactivity was examined in 10 healthy volunteers. Ketanserin was administered as an intravenous bolus of 10 mg followed by an infusion of 6mg/h. Before administration CBF was measured by single photon emission computerized tomography (SPECT) of inhaled¹³³ Xenon. Then arterial CO₂ tension was subsequently decreased by voluntary hyperventilation and increased by breathing an air/CO₂ mixture. The relative changes in CBF induced by the changes in arterial CO₂ tension were estimated by the cerebral arterio-venous oxygen content difference method. One hour following the start of ketanserin infusion the SPECT measurement and CO₂ manipulations were repeated.The CO₂ reactivity (expressed as the slope of the regression line of the linear relation between CBF and PaCO₂), was unchanged, i.e. 3.2%/0.1 kPa before ketanserin and 4. 1%/0.1 kPa during ketanserin, respectively. Using regression lines from a semi-logarithmic plot the CO₂ reactivity was also unchanged 3.4%/0.1 kPa and 3.5%/0.1 kPa, respectively. Ketanserin did not change CBF. The cerebral oxygen metabolism (CMRO₂) was decreased 19% one hour after the start of infusion of ketanserin.In conclusion administration of ketanserin in a clinically relevant dose to healthy volunteers does not change the regional CBF not the cerebrovascular CO₂ reactivity, but a decrease in CMRO₂ was observed. However further studies are needed to clarify whether ketanserin in fact has a depressing effect on CMRO₂ or whether the different results are caused by methodological errors or stocastic variation.     

Cerebral blood flow and oxidative brain metabolism during and after moderate and profound arterial hypoxaemia

Summary In anaesthetized artificially ventilated dogs, the effect of graded arterial hypoxaemia on cerebral blood flow (CBF) and on the oxidative carbohydrate metabolism of the brain was tested. It is shown that the hypoxic vasodilatory influence on cerebral vessels is present even atmoderate systemic hypoxaemia, provided that PaCO₂ is kept within normal limits. At PaO₂ of about 50 Torr, CBF increased from 56.6 to 89.7 ml/100 g/min. With increasing cerebral hyperaemia (CBF increased to 110.9 ml/100 g/min, at PaO₂ of 30 Torr), CMRO₂ (4.2 ml/100 g/min) was not significantly raised above its normal level (4.7 ml/100 g/min) even with profound arterial hypoxaemia. This shows that CMRO₂ levels are poor indices of hypoxic hypoxia. A disproportionately high increase in cerebral glucose uptake (CMR glucose levels rose from 4.4 to 10.4 mg/100 g/min) and enhanced cerebral glycolysis (CMR lactate changed from 0.2 to 1.6 mg/100 g/min) at moderately reduced PaO₂ (50 Torr) indicated early metabolic changes which became more marked with further falls in arterial oxygen tension. However, 60 minutes after restoration of a normal PaO₂ level, CBF and brain metabolism were found to have completely recovered. It is concluded that a short period of profound systemic hypoxaemia does not produce long lasting metabolic and circulatory disorders of the brain provided the cerebral perfusion pressure does not vary, and is kept at normal levels.     

EFFECT OF KETANSERIN ON GLOBAL CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN METABOLISM DURING MIDAZOLAM-FENTANYL OR ISOFLURANE ANAESTHESIA

We have studied the effect of ketanserin on cerebral blood flow(CBF), cerebral oxygen metabolism (CMRO₂) and cerebrovascularcarbon dioxide reactivity in 19 adult patients undergoing lumbardisc operation – 10 during midazolam-fentanyl anaesthesia(group A) and nine during isoflurane anaesthesia (group B).Measurements were made in each patient whilst awake, duringanaesthesia, during anaesthesia with ketanserin and during anaesthesiawith ketanserin and hyperventilation. CBF was measured by thei. v. xenon-133 technique. CMRO₂ was calculated as the productof CBF and the cerebral arterio-venous oxygen content difference.In the awake state, CBF was 52 and 51 ml/100g min_–1 andCMRo₂ 3.8 and 3.5 ml/100 g min_–1 in groups A and B, respectively.After induction of anaesthesia, CBF decreased 37% in group Aand 22% in group B (P < 0.05); CMRo₂ decreased 26% in groupA and 51% in group B (P < 0.05). Adding ketanserin did notchange CBF or CMRo₂ in either group. The carbon dioxide reactivityof the cerebral vessels during anaesthesia with ketanserin was15.4%kPa^–1 in group A and 24%kPa^–1 in group B. Weconcluded that ketanserin, in a clinically recommended dose,administered during midazolam-fentanyl or isoflurane anaesthesiahad no effect on global CBF, CMRo₂ or the relationship betweenthe two factors. Cerebrovascular carbon dioxide reactivity waspreserved.     

Effect of ketanserin on cerebral blood flow autoregulation in healthy volunteers

Summary The effect of a clinically relevant dose of ketanserin (10 mg as a bolus followed by an infusion of 6mg/h) on cerebral blood flow (CBF) and CBF autoregulation was examined in 12 healthy volunteers. Changes in CBF were estimated by the cerebral arteriovenous-oxygen saturation difference method, while mean arterial blood pressure (MABP) was increased by norepinephrine and decreased by ganglionic blockade (trimethaphan camphosulphonate) combined with lower body negative pressure one hour after the infusion of ketanserin. During ketanserin infusion, MABP fell insignificantly by 2.5 mmHg (6 to –2), while CBF rose insignificantly by 5 ml/100 g/min. Autoregulation was preserved in all volunteers. CO₂-correction factors from 0 to 4.6% CBF/0.1 kPa were used. The lower limit of CBF autoregulation was 82 mmHg (80–86) with an SE of 3 mmHg (1–5) similar to a previous control group of healthy volunteers. Aside from a major decrease in MABP in one subject, no adverse side effects were observed.The present study shows that CBF autoregulation is maintained during ketanserin infusion.     

Sequential changes in cerebral blood flow and metabolism in patients with subarachnoid haemorrhage

Summary Haemodynamic and metabolic sequences were investigated in nine patients having subarachnoid haemorrhage (SAH) up to 3 months following aneurysmal rupture, using positron emission tomography (PET). In the pre-spasm stage (2–4 days after SAH) cerebral blood flow (CBF, ml/100 ml/min) was 45±11, the cerebral metabolic rate of oxygen (CMRO₂, ml/100 ml/min) was 2.68±0.50, and cerebral blood volume (CBV, ml/100 ml) was 5.5±1.2. CBF within the normal range and a relatively low CMRO₂, indicated relative hyperaemia. This was possibly due to the direct toxic effect of SAH on the brain metabolism. CBV was considerably elevated. The spasm stage (6–15 days after SAH) showed CBF values of 39±7, CMRO₂ values of 2.42±0.50, and CBV values of 5.4±1.7. CBF decreased significantly (p<0.05 vs pre-spasm stage), and CMRO₂ also tended to decrease, while they were coupling. It is likely that this may have been induced by vasospasm. Thereafter, the PET parameters normalized gradually. During all the stages studied, significant laterality of the PET parameters was not observed. This may be because SAH and vasospasm provide diffuse pathophysiological conditions for the entire brain and cerebral arteries.     

Cerebral glucose and energy metabolism,cerebral oxygen consumption,and blood flow in arterial hypoxaemia

Summary The influence of moderately reduced arterial oxygen tension (aPO₂ of about 45 Torr) on the metabolism and the blood flow of the brain was tested in 20 anaesthetized, artificially ventilated normotensive, normocapnic beagle dogs. It is demonstrated that the decrease in systemic oxygen delivery to the brain is countered by an appropriate increase in flow (CBF being 60.3 ml/100 g min at normoxia and 84.5 mg/100 g min m hypoxaemia) which maintained the cerebral oxygen consumption unchanged (CMRO₂ 3.80 versus 3.32 ml/100 g min). The cortical tissue content of energy-rich phosphates such as ATP, ADP, AMP, and phosphocreatine was also found to be unaltered. Neuropathological examinations excluded any hypoxic cell damage. This reactive vasodilatory reaction of the cerebral vessels is apparently a sensitive regulatory process which protects the brain against marked oxygen lack. However, a normal carbohydrate metabolism is not restored by this cerebrovascular mechanism. For, significantly increased CMRlactate (0.32 versus 1.46 ml/100 g min) indicated raised cerebral glycolysis, and the tissue metabolites of glucose suggested an increased glycolytic flux in the brain. It is concluded that in moderate arterial hypoxaemia, which is not uncommon in clinical practice, cerebral blood flow plays an effective homeostatic role in preventing a disturbance of the energy metabolism of the brain.     

The acute effect of nimodipine on cerebral blood flow,its CO2 reactivity,and cerebral oxygen metabolism in human volunteers

Summary The present study was undertaken in 8 healthy volunteers to examine the effect of a clinically relevant dose of nimodipine (NIM) (15 and 30 microgram/kg/h) on CBF, its CO₂ reactivity, and CMRO₂. Mean arterial blood pressure (MABP) was measured intra-arterially. Regional CBF was measured by SPECT of inhaled Xenon-133. During the CO₂ reactivity tests changes in CBF were estimated by the arterio-venous-oxygen-difference method. Median CBF was 52 ml/ 100 g/min (48–53) with a normal regional distribution, and median baseline MABP was 96 mmHg (92–99). MABP was slightly reduced, by 8 mmHg (7–9), and 9 mmHg (4–11) after infusion of NIM for 2 and 4 hours, respectively. CBF, however, remained constant, although correction for changes in PaCO₂, revealed a slight increase after 4 hours (p=0.08). CMRO2 was 3.5 ml/100 g/min (3.2–3.5) and was not changed by the infusion of NIM. At arterial CO₂ tensions ranging from 4.0 to 6.5 Kpa the CO₂ reactivity was 3.0% CBF/ 0.1 kPa (2.6–3.7) and decreased significantly to 2.6% CBF/0.1 kPa (1.8–3.2) after the infusion of NIM for 3 hours (p=0.02). The median slope of the LnCBFsat/PaCO₂ relationship was 1.5 at baseline compared to 1.3 after NIM (p<0.01). No side effects were observed.The present study shows a decreased CO₂ of the cerebral vessels and a maintained coupling of CBF and CMRO₂ during the infusion of nimodipine.     

Measurements of CO2 reactivity and barbiturate reactivity in patients with severe head injury

Summary In nine patients with severe head injury subjected to continuous hyperventilation and barbiturate coma treatment with pentobarbitone, the regional cerebral blood flow was measured as initial slope index (ISI) with a 32 channel Cerebrograph, and cerebral metabolic rate of oxygen (CMRO₂) was calculated as the product of mean global CBF and the arterio-venous oxygen content difference.CBF was measured at strategic intervals either to follow the treatment (hyperventilation and/or pentobarbitone), or to determine whether these principles of treatment should be intensified or reduced. During the flow measurements the CO₂ reactivity and the reactivity to a bolus injection of thiopentone 5 mg/kg were calculated globally and regionally. The global CO₂ reactivity was calculated as relative (%change CBF/PaCO₂ mmHg) and absolute (CBF/ PaCO₂ mmHg), and the reactivity to barbiturate was calculated globally as CMRO₂, and regionally as %change rCBF.The absolute and relative global CO₂ reactivities correlated positively with the mean. CBF values before hyperventilation, and the global barbiturate reactivity was dependent on the CMRO₂ value obtained before hyperventilation. However, at low levels of CMRO₂ ranging between 1.0 and 1.1 ml O₂ the barbiturate reactivity was abolished. The regional studies of CBF, CMRO₂, CO₂ reactivity and barbiturate reactivity gave important information, when decisions concerning therapeutic regimes with special reference to hyperventilation and sedation with pentobarbitone were necessary.     

Quantitative cerebral blood flow and metabolism determination in the first 48 hours after severe head injury with a new dynamic spect device

SummaryObjective To determine cerebral blood flow (CBF) and metabolism in the acute phase after severe head injury by a new dynamic SPECT device using¹³³Xenon and to evaluate a possible role of CBF and metabolism in the determination of prognosis.Design Prospective studySetting General intensive care unit in a universitary teaching hospitalSubjects 23 severely head injured patients having CT scan and CBF determination, intracranial pressure (ICP) and jugular bulb oxygen saturation monitoring in the first 48 hours.Measurements and main results CBF varied from 18.0 to 60.0 ml/100 g/min. No correlation was found between early CBF and severity of trauma evaluated with the Glasgow Coma Score (GCS) (F = 2.151, p = 0.142) and between CBF and prognosis at 6 months evaluated with Glasgow outcome score (GOS) (F = 0.491, p = 0.622; r_s = 0.251, p = 0.246). CMRO₂ was depressed in relation to the severity of injury, specifically ranging from 0.9±0.5 ml/ 100 g/min in patients with GCS 3 to 1.7 ±0.8 ml/100 g/min in patients with GCS 6–7. In no patient with a CMRO₂ less than 0.8 ml/100 g/min was a good outcome observed. A significant correlation was found between GCS and GOS (r_s = 0.699, p = 0.0002), between CMRO₂ and GOS (F = 4.303, p = 0.031; r_s = 0.525, p = 0.013) and between AJDO₂ and GOS (F = 3.602, p = 0.046; r_s = 0.491, p = 0.017). Fronto-occipital ratio (F/O) of CBF distribution was significantly lower than normal values (²=18.658, p = 0.001) but did not correlate either with prognosis (² = 1.626, p = 0.443) or with severity (² = 1.913, p = 0.384).Conclusions CBF in the first 48 hours after trauma varies within a large range of values and is not correlated with severity and prognosis. Clinical evaluation with GCS and CMRO₂ are much more reliable indicators of severity of head trauma and have a significant role in the determination of prognosis. F/O ration is significantly altered from normal values confirming post-traumatic hypofrontalism but does not correlate with severity and prognosis.     

CO2 and indomethacin vasoreactivity in patients with head injury

Summary The purpose of this study was to compare the effect of hyper-ventilation and indomethacin on cerebral circulation, metabolism and pressures in patients with acute severe head injury in order to see if indomethacin may act supplementary to hyperventilation. Fourteen severely head injured patients entered the study. Intracranial pressure (ICP), mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored continuously. Within the first four days after the trauma the CO₂ and indomethacin vasoreactivities were studied by measurements of cerebral blood flow (CBF) (Cerebrograph 10a, intravenous¹³³Xe technique) and arterio-venous difference of oxygen (AVdO₂). Ischaemia was evaluated from changes in CBF, saturation of oxygen in the jugular bulb (SvjO₂), lactate and lactate/oxygen index (LOI). Data are presented as medians and ranges, results are significant unless otherwise indicated. Before intervention ICP was well controlled (14.8 (9–24) mmHg) and basic CBF level was 39.1 (21.6–75.0) ml/100 g/min). The arterio-venous oxygen differences were generally decreased (AVdO₂ = 4.3 (1.8–8.1) ml/100 ml) indicating moderate luxury perfusion. Levels of CMRO₂ were decreased (1.54 (0.7–3.2) ml/100 g/min) as well.Duringhyperventilation (APaCO₂ = 0.88 (0.62–1.55) kPa) CBF decreased with 11.8 (–33.4–29.7) %/kPa and ICP decreased with 3.8 (0–10) mmHg. AVdO₂ increased 34.0 (4.0–139.2) %/kPa, MABP was unchanged, CMRO₂ and CPP increased (CPP = 3.9 (–10–20) mmHg). AVD (lactate) and LOI were unchanged. No correlations between CBF responses to hypocapnia and outcomes were observed.An i.v. bolus dose ofindomethacin (30 mg) decreased CBF 14.7 (–16.7–57.4) % and ICP decreased 4.3 (–1–17) mmHg. AVdO₂ increased 27.8 (–40.0–66.7)%, MABP (MABP = 4.9 (–2–21) mmHg) and CPP (CPP = 8.7 (3–29) mmHg) increased while CMRO₂ was unchanged. No changes in AVd (lactate) and LOI indicating cerebral ischaemia were found.Compared to hyperventilation (changes per 1 kPa, at PaCO₂ level = 4.05 kPa) the changes in MABP, CPP and CBF were significantly greater after indomethacin, while the changes in AVdO₂, ICP, SvjO₂, and LOI were of the same order of magnitude.Nocorrelation between relative reactivities to indomethacin and CO₂, evaluated from changes in CBF and AVdO₂, or between the decrease in ICP after the two procedures were found. Thus, some patients reacted to indomethacin but not to hyperventilation, and vice versa.These results suggest that indomethacin and hyperventilation might act independently, or in a complementary fashion in the treatment of patients with severe head injury.     

Zum Einfluß der präischämischen Blutzuckerkonzentration auf Hämodynamik und regionale Organdurchblutung während und nach kardiopulmonaler Reanimation (CPR) beim Schwein

Blood glucose alterations prior to cerebral ischaemia are associated with poor neurologic outcome, possibly due to extensive lactic acidosis or energy failure. Cerebral effects of hyper- or hypoglycaemia during cardiopulmonary resuscitation (CPR) are less well known. In addition, little information is available concerning cardiac effects of blood glucose alterations. The aim of this study was to evaluate the effects of pre-cardiac-arrest hypo- or hyperglycaemia compared to normoglycaemia upon haemodynamics, cerebral blood flow (CBF) and metabolism (CMRO₂), and regional cardiac blood flow during CPR subsequent to 3?min of cardiac and respiratory arrest and after restoration of spontaneous circulation. Methods. After approval by the State Animal Investigation Committee, 29 mechanically ventilated, anaesthetised pigs were instrumented for haemodynamic monitoring and blood flow determination by the radiolabeled microsphere technique. The animals were randomly assigned to one of three groups: in group I (n=9) blood glucose was not manipulated; in group II (n=10) blood glucose was increased by slow infusion of 40% glucose to 319±13 mg/dl; in group III (n=10) blood glucose was lowered by careful titration with insulin to 34±2 mg/dl. After 3 min of untreated ventricular fibrillation and respiratory arrest, CPR (chest compressor/ventilator (Thumper^®) and epinephrine infusion) was commenced and continued for 8?min. Thereafter, defibrillation was attempted, and if successful, the animals were observed for another 240?min. Cerebral perfusion pressure (CPP), CBF, CMRO₂, coronary perfusion pressure (CorPP), and regional cardiac blood flow were determined at control, after 3?min of CPR, and at 10, 30, and 240?min post-CPR. Results. In group I, 4/9 animals (44%) could be successfully resuscitated; in group II 4/10 (40%); and in group III 0/10 (0%). Prior to cardiac arrest, mean arterial pressure, CPP, and CorPP in group III were significantly lower compared to groups I and II. In group I, CPP during CPR was 26±6?mmHg; CBF 31±9?ml/min/100?g CMRO₂ 3.8±1.2 ml/min/100?g; CorPP 18±5 mmHg; and left ventricular (LV) flow 35±15 ml/min/100 g. In group II: CPP=21±5; CBF 21±7; CMRO₂ 1.8±0.8; CorPP 16±6; and LV flow 22±9; and in group III: CPP 15±3; CBF 11±8; CMRO₂ 1.5±1.1; CorPP 4±2; and LV flow 19±10. During the 240-min post-resuscitation period, there were no differences in CBF, CMRO₂, or LV flow between groups I and II. Conclusion. Hypoglycaemia prior to cardiac arrest appears to be predictive for a poor cardiac outcome, whereas hyperglycaemia does not impair resuscitability compared to normoglycaemia. In addition, hyperglycaemia did not affect LV flow, CBF, or CMRO₂. However, it has to be kept in mind that haemodynamics and organ blood flow do not permit conclusions with respect to functional neurologic recovery or histopathologic damage to the brain, which is very likely to be associated with hyperglycaemia.     

Cerebral blood flow and oxygen metabolism measured with the Kety–Schmidt method using nitrous oxide

Background: The Kety–Schmidt method is the reference method for measuring global cerebral blood flow (CBF), cerebral metabolic rates (CMR) and flux, especially where scanners are unavailable or impractical. Our primary objective was to assess the repeatability of the Kety–Schmidt method in a variety of different approaches using inhaled nitrous oxide (N₂O) as the tracer, combined with photoacoustic spectrometry. A secondary objective was to assess the impact of this tracer on the systemic vascular concentration of nitrite (NO₂^?). Methods: Twenty‐nine healthy male volunteers underwent 61 CBF measurements by breathing a normoxic gas mixture containing 5% N₂O until tension equilibrium. Paired blood samples were collected from an arterial and a jugular bulb catheter in the saturation or desaturation phase, by continuous or the discontinuous sampling. N₂O concentration was measured with photoacoustic spectrometry after equilibration of blood samples with air. CBF was calculated by the Kety–Schmidt equation. CMR of oxygen (CMRO₂) was determined by the Fick principle. NO₂^? in plasma and red blood cells (RBC) was measured by ozone‐based chemiluminescence. Results: The most robust approach for CBF measurement was achieved by discontinuous sampling in the desaturation phase [CBF, 64 (95% confidence interval, 59–71 ml)] 100 g/min; CMRO₂ 1.8 (1.7–2.0) μmol/g/min). The tracer did not influence plasma or RBC NO₂^? (P>0.05 vs. baseline). Conclusion: These findings confirm the reliability and robustness of the Kety–Schmidt method using inhaled N₂O for the measurement of global CBF and CMR. At the low tracer concentration used, altered NO metabolism is unlikely to have affected cerebral haemodynamic function.     

Effect of 1 or 2 MAC isoflurane with or without ketanserin on cerebral blood flow autoregulation in man

We have studied the effect of 1 or 2 MAC isoflurane with orwithout ketanserin on cerebral blood flow (CBF), cerebral oxygenmetabolism (CMRO₂) and CBF autoregulation in 20 adult patientsundergoing lumbar disc surgery. Ten patients received ketanserinand 10 isotonic saline. CBF measurements were started after1 h of infusion of saline or ketanserin. The patients were anaesthetizedwith thiopentone 5 mg kg^–1 followed by isoflurane. During1 MAC of isoflurane, baseline values were recorded and thenCBF autoregulation was examined (mean arterial pressure increasedby about 30% with angiotensin). The sequence was repeated with2 MAC of isoflurane. CBF was measured by the i.v. xenon-133technique. CMRo₂ was calculated as the product of CBF and thecerebral arterio-venous oxygen content difference. Ketanserinhad no effect on CBF, CMRo² or CBF autoregulation during isofluraneanaesthesia, therefore all patients were pooled for evaluationof the effect of isoflurane. Increasing isoflurane anaesthesiafrom 1 to 2 MAC increased mean CBF from 41 to 49 ml /100 g min^–1(P<: 0.01) and decreased mean CMRo₂ from 1.5 to 1.1 ml/100g min^–1 (P < 0.001) and thus abolished the couplingbetween flow and metabolism. The CBF autoregulation test indicatedthat autoregulation was disrupted at 2 MAC, but not during 1MAC isoflurane anaesthesia. (Br. J. Anaesth. 1994; 72: 66–71)     

Comparison of moderate hyperventilation and mannitol for control of intracranial pressure control in patients with severe traumatic brain injury – a study of cerebral blood flow and metabolism

Summary Objective. To compare the respective effects of established measures used for management of traumatic brain injury (TBI) patients on cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO₂), glucose (CMRGlc) and lactate (CMRLct). Methods. Thirty-six patients suffering from severe traumatic brain injury (TBI) were prospectively evaluated. In all patients baseline assessments were compared with that following moderate hyperventilation (reducing PaCO₂ from 36 ± 4 to 32 ± 4 mmHg) and with that produced by administration of 0.5 gr/kg mannitol 20% intravenously. Intracranial and cerebral perfusion pressure (ICP, CPP), CBF and arterial jugular differences in oxygen, glucose and lactate contents were measured for calculation of CMRO₂, CMRGlc and CMRLct. Results. Following hyperventilation, CBF was significantly reduced (P < 0.0001). CBF remained most often above the ischemic range although values less than 30 ml·100 gr⁻¹·min⁻¹ were found in 27.8% of patients. CBF reduction was associated with concurrent decrease in CMRO₂, anaerobic hyperglycolysis and subsequent lactate production. In contrast, mannitol resulted in significant albeit moderate improvement of cerebral perfusion. However, administration of mannitol had no ostensible effect either on oxidative or glucose metabolism and lactate balance remained mostly unaffected. Conclusions. Moderate hyperventilation may exacerbate pre-existing impairment of cerebral blood flow and metabolism in TBI patients and should be therefore carefully used under appropriate monitoring. Our findings rather support the use of mannitol for ICP control.     

Combined effects of propofol and mild hypothermia on cerebral metabolism and blood flow in rhesus monkey: a positron emission tomography study

Purpose Propofol reduces the cerebral metabolic rate for oxygen (CMRO₂), regional CMRO₂ (rCMRO₂), cerebral blood flow (CBF), and regional CBF (rCBF), but maintains the coupling of cerebral metabolism and blood flow. Under mild to moderate hypothermia, the coupling is maintained, while rCBF is reduced, but no direct measurement of rCMRO₂ has yet been reported. This study aimed to evaluate the effects of propofol under normothermic and mild hypothermic temperatures upon rCMRO₂, rCBF, and their regional coupling, through direct measurement by positron emission tomography. Methods Rhesus monkeys were anesthetized with 65% nitrous oxide and propofol. Then rCBF and rCMRO₂ were measured under four sets of conditions: infusion of a low-propofol dose (12 mg·kg⁻¹·h⁻¹) at normothermic temperatures (38°C), a high dose (25 mg·kg⁻¹·h⁻¹) at normothermic temperatures, a low dose under mild hypothermia (35°C), and a high dose under mild hypothermia. The ratio of rCBF/rCMRO₂ was calculated from these data. Results Reductions in CMRO₂ and rCMRO₂ in most regions were associated with two factors: the higher propofol dose and the induction of hypothermia, but there was no interaction between these factors. Concerning blood flow, no significant reduction was observed, except for CBF by the induction of hypothermia. The ratio of rCBF/rCMRO₂ was constant in this study setting. Conclusion During propofol anesthesia, it is possible to reduce cerebral metabolism throughout the entire brain as well as in any brain region by increasing the propofol dose or inducing hypothermia. The concurrent use of these two interventions has an additive effect on metabolism, and can be considered as safe, as their combination does not impair the coupling of cerebral metabolism and blood flow.     

No influence of the endothelin receptor antagonist bosentan on basal and indomethacin-induced reduction of cerebral blood flow in pigs

BACKGROUND: The mechanism behind indomethacin-induced cerebral vasoconstriction is incompletely understood. We tested the hypothesis that the mixed endothelin-1 receptor antagonist bosentan would modify or prevent indomethacin-induced reduction of CBF in the anaesthetized pig. Furthermore, we investigated the effect of bosentan on resting CBF and CMRO2. METHODS: Twelve pigs were randomized in two groups of six, and received either bosentan and indomethacin (group 1), or placebo and indomethacin (group 2). Anaesthesia was induced with ketamine and midazolam and maintained with fentanyl, nitrous oxide and pancuronium. Baseline measurements of CBF and CMRO2 were performed before intravenous bolus injection of bosentan (10 mg/kg) or placebo (0.9% NaCl). The second CBF and CMRO2 measurement was performed 30 min after administration of bosentan/placebo. A 40-min infusion of indomethacin (0.05 mg/kg/min) was administered and the third CBF and CMRO2 measurement was performed 80 min after administration of bosentan/placebo. Independently, pharmacokinetic data of bosentan were generated in four pigs. RESULTS: In group 1, baseline CBF was 55 +/- 7 ml/100 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/min (P < 0.002). No significant changes in CMRO2 were observed. In group 2, a significant increase in MABP was observed after administration of indomethacin. No change in MABP was observed in the bosentan-treated animals. Total plasma concentrations of bosentan at the time of the first and the second PET measurement were 3.9 and 1.4 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/ml. CONCLUSION: These findings indicate that endothelin receptor stimulation is not involved in indomethacin-induced cerebral vasoconstriction or maintenance of cerebrovascular tone in the anaesthetized pig. However, our results suggest that the increase in MABP is mediated through endothelin receptors.     

Cerebral Blood Flow and Oxygen Uptake in Endotoxic Shock. An Experimental Study in Dogs

Cerebral blood flow (CBF), cerebral oxygen uptake (CMRo₂) and central haemodynamics in anaesthetized dogs with controlled ventilation were studied at intervals for 2 h following an intravenous injection of E. coli endotoxin, 1.0–1.5 mg/kg. CBF showed a 30% decrease within 15 min after the endotoxin administration, while the arterial blood pressure was still not markedly depressed. Autoregulation to arterial blood pressure changes was maintained during endotoxinaemia and the cerebrovascular reaction to changes in arterial carbon dioxide tension (Paco₂) depressed. Normocapnic animals (PacO₂ ≥ 4.0 kPa) showed an increase in CMRO₂ of over 40%, that was obvious 1 h after the administration of endotoxin. The intracranial pressure was decreased within 5 min of the administration of endotoxin irrespective of the prevailing arterial blood pressure. Thereafter, it was raised above the control level. Two hours after endotoxin increased protein concentrations in cerebrospinal fluid were seen, results compatible with blood-brain barrier damage and penetration of other substances; e.g. monoamines released during endotoxinaemia could thus be expected to have a direct influence on both cerebral blood flow and metabolism.     

The effect of indomethacin upon cerebral blood flow in healthy volunteers

Summary In a randomized study of healthy volunteers indomethacin bolus injection followed by continuous infusion decreased CBF from normal levels ranging from 45 to 80 ml/100 g/min to levels ranging from 24 to 57 ml/100 g/min. These low levels were sustained during a six hour infusion period. Periods of hypoxia during inhalation of 17% oxygen and hypercapnia during inhalation of 2–4% CO₂ normalized CBF.     

EFFECTS OF ALTHESIN ON CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN MAN

Cerebral circulation and metabolism during Althesin anaesthesiawere studied in seven healthy patients. Althesin was given ina single dose of 0.1 ml/kg and thereafter infused at a constantrate of 0.3 ml/kg/h. During Althesin infusion, the cerebralblood flow (CBF), the cerebral metabolic rate for oxygen (CMRo₂)were 29 ±10 ml/100 g/min and 1.7 ± 0.4 ml/100g/min, respectively. These values were significantly differentfrom those obtained in awake subjects in our laboratory (CBF:46±7 ml/100 g/min; CMRo₂: 3.1 ±0.6 ml/100 g/min).During CBF measurement, the mean cerebral perfusion pressure,cerebral vascular resistance (CVR) and arterial carbon dioxidetension (Pa_CO2) were 89±16mmHg,3.4±1.3 mm Hg/ml/100g/min, and 36±9mmHg, respectively. The relationship betweenCBF and .Pa_CO2 was studied and it was found that during Althesinanaesthesia reactivity of cerebral vessels to the alterationof Pa_CO2 was maintained. It is concluded that Althesin causedcerebral metabolic depression which was accompanied by a decreasein CBF and an increase in CVR.     

Preoperative high dose methylprednisolone attenuates the cerebral response to deep hypothermic circulatory arrest.

OBJECTIVE: The aim of this study was to assess the effects of preoperative high dose methylprednisolone on cerebral recovery following a period of deep hypothermic circulatory arrest (DHCA). METHODS: Sixteen 1-week-old piglets were randomized to placebo (n=8), or 30 mg/kg intramuscular methylprednisolone sodium succinate (MPRED) given at 8 and 2 h before induction of anaesthesia. All piglets underwent cardiopulmonary bypass, cooling to 18 degrees C, 60 min of circulatory arrest followed by 60 min of reperfusion and rewarming. The radiolabelled microsphere method was used to determine the global and regional cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) at baseline before DHCA and after 60 min of reperfusion. RESULTS: In controls, mean global CBF (+/-1 standard error) before DHCA was 53.7+/-2.4 ml/100 g per min and fell to 23.8+/-1.2 ml/100 g per min following DHCA (P<0.0001). This represents a post-DHCA recovery to 45.1+/-3.3% of the pre-DHCA value. In the MPRED group recovery of global CBF post-DHCA was significantly higher at 63.6+/-5.2% of the pre-DHCA value (P=0.009). The regional recovery of CBF in the cerebellum, brainstem and basal ganglia was 80, 75 and 69% of pre-DHCA values in the MPRED group respectively compared to 66, 60 and 55% in controls (P<0.05). Global CMRO(2) in controls fell from 3.9+/-0.2 ml/100 g per min before to 2. 3+/-0.2 ml/100 g per min after DHCA (P=0.0001). This represents a post-DHCA recovery to 58.6+/-4.4% of the pre-DHCA value. In the MPRED group, however, recovery of global CMRO(2) post-DHCA was significantly higher at 77.9+/-7.1% of the pre-DHCA value (P=0.04). CONCLUSIONS: Treatment with high dose methylprednisolone at 8 and 2 h preoperatively attenuates the normal cerebral response to a period of deep hypothermic ischaemia. This technique may therefore offer a safe and inexpensive strategy for cerebral protection during repair of congenital heart defects with the use of DHCA.