Moderate Hypotension Research Articles

Significance of endogenous opioids in the maintenance of cerebral and spinal vascular CO 2-sensitivity in deep hemorrhagic hypotension

High CO 2-sensitivity, one of the major characteristics of the cerebrovascular bed, has been shown to be influenced by a variety of factors. There are no reports, however, on the involvement of the endogenous opioid peptides in the modulation of the CO 2-sensitivity of the cerebral and spinal cord vessels, either in normotensive or, in hypotensive conditions. The effect of general opiate receptor blockade (1.0 mg/kg naloxone, i.v.) on regional cerebrovascular CO 2-sensitivity was studied with radiolabeled microspheres in 10 distinct brain and spinal cord regions of the anesthetized cat. The CO 2-induced flow changes were investigated in normotensive, in moderately hypotensive (MAP=80 mmHg) and in deep hypotensive cats (MAP=40 mmHg). The systemic arterial pressure was lowered by hemorrhage. In the normotensive cats, opiate receptor blockade caused no changes in the vascular CO 2-sensitivity in the investigated cerebral and spinal cord regions. In moderate hypotension, cerebral and spinal CO 2-sensitivity was significantly reduced by the hemorrhage itself, but remained unaffected by the naloxone administration. In deep hemorrhagic hypotension, however, general opiate receptor blockade resulted not only in a further reduction of the already impaired CO 2-sensitivity, but even in a reversal of the effect of CO 2 from flow increase to flow decrease. These results indicate that endogenous opioid peptides, which do not seem to influence cerebrovascular reactions in steady-state, normotensive conditions, may contribute significantly to the maintenance of the normal vasodilatory response of the cerebral and spinal cord vessels to CO 2 during hemorrhage-induced deep arterial hypotension.

Fos expression in spinally projecting neurons after hypotension in the conscious rabbit

Hypotension produces a reflex increase in the activity of sympathetic vasomotor nerves. Studies in anaesthetised animals have established that neurons in the rostral ventrolateral medulla (RVLM) that project directly to sympathetic vasomotor preganglionic neurons in the spinal cord are a critical component of the central pathways mediating this reflex response. There are also neurons in supramedullary regions (the A5 area in the pons and the paraventricular nucleus (PVN) in the hypothalamus), however, that project directly to the sympathetic vasomotor outflow. The aim of this study was to identify and map neurons within the A5 area and PVN, as well as in the RVLM, which may contribute to the reflex sympathoexcitatory response to a hypotensive challenge in conscious rabbits. In a preliminary operation, a retrogradely transported tracer was injected into a site centred on the intermediolateral cell column in the upper lumbar spinal cord. After a waiting period of at least 1 week, a moderate hypotension (decrease in arterial pressure of approximately 20 mm Hg) was induced in conscious rabbits for 60 min by continuous infusion of sodium nitroprusside. In confirmation of previous studies, hypotension resulted in the expression of Fos in the RVLM, the A5 area and PVN. There were also retrogradely labelled neurons in all these regions. In both the RVLM and A5 area, approximately 40% of the retrogradely labelled neurons were also immunoreactive for Fos. In contrast, in the PVN the proportion of retrogradely labelled neurons that were also Fos-positive was much less (approximately 6%). This study has demonstrated that, in the conscious rabbit, a significant proportion of spinally projecting neurons within discrete regions in the RVLM and A5 area are activated by hypotension (as indicated by Fos expression). In the PVN, only a very small proportion of spinally projecting neurons are activated by hypotension, and thus these neurons appear to be regulated primarily by inputs other than baroreceptor inputs.

Variations in CBF during hypotension and in cortical eNOS in rats

Variations in the height of the autoregulatory curve near the lower limit present the intriguing suggestion that there are local differences in cortical vascular regulation. We suspect that these variations are related to local variations in the amount of cortical eNOS, [eNOS] br. Laser Doppler flowmetry (LDF) monitoring of CBF in rat cortex during hemorrhagic hypotension revealed that the CBF at a mean arterial pressure of 70 mmHg (%CBF 70) was highly variable and distributed normally. Both paradoxical rises in CBF and pressure-passive CBF were common during moderate hypotension. In other experiments, similar variations in the concentration of eNOS, [eNOS] br, were observed in brain samples of similar volume to the volume sensed by LDF and differences in %CBF 70 were noted in different regions of the same animal's cortex. These observations suggest the surprising possibility that cortical variations in the amount of eNOS protein, not its regulation, relate to variations in the CBF response to moderate hypotension.

Delayed hemorrhagic hypotension exacerbates the hemodynamic and histopathologic consequences of traumatic brain injury in rats.

Alterations in cerebral autoregulation and cerebrovascular reactivity after traumatic brain injury (TBI) may increase the susceptibility of the brain to secondary insults, including arterial hypotension. The purpose of this study was to evaluate the consequences of mild hemorrhagic hypotension on hemodynamic and histopathologic outcome after TBI. Intubated, anesthetized male rats were subjected to moderate (1.94 to 2.18 atm) parasagittal fluid-percussion (FP) brain injury. After TBI, animals were exposed to either normotension (group 1: TBI alone, n = 6) or hypotension (group 2: TBI + hypotension, n = 6). Moderate hypotension (60 mm Hg/30 min) was induced 5 minutes after TBI or sham procedures by hemorrhage. Sham-operated controls (group 3, n = 7) underwent an induced hypotensive period, whereas normotensive controls (group 4, n = 4) did not. For measuring regional cerebral blood flow (rCBF), radiolabeled microspheres were injected before, 20 minutes after, and 60 minutes after TBI (n = 23). For quantitative histopathologic evaluation, separate groups of animals were perfusion-fixed 3 days after TBI (n = 22). At 20 minutes after TBI, rCBF was bilaterally reduced by 57% +/- 6% and 48% +/- 11% in cortical and subcortical brain regions, respectively, under normotensive conditions. Compared with normotensive TBI rats, hemodynamic depression was significantly greater with induced hypotension in the histopathologically vulnerable (P1) posterior parietal cortex (P < 0.01). Secondary hypotension also increased contusion area at specific bregma levels compared with normotensive TBI rats (P < 0.05), as well as overall contusion volume (0.96 +/- 0.46 mm(3) vs. 2.02 +/- 0.51 mm(3), mean +/- SD, P < 0.05). These findings demonstrate that mild hemorrhagic hypotension after FP injury worsens local histopathologic outcome, possibly through vascular mechanisms.

Effect of initially limited resuscitation in a combined model of fluid-percussion brain injury and severe uncontrolled hemorrhagic shock.

Studies of isolated uncontrolled hemorrhage have indicated that initial limited resuscitation improves survival. Limited resuscitation has not been studied in combined traumatic brain injury and uncontrolled hemorrhage. In this study the authors evaluated the effects of limited resuscitation on outcome in combined fluid-percussion injury (FPI) and uncontrolled hemorrhage. Twenty-four swine weighing 17 to 24 kg each underwent FPI (3 atm) and hemorrhage to a mean arterial pressure (MAP) of 30 mm Hg in the presence of a 4-mm aortic tear. Group I (nine animals) was initially resuscitated to a goal MAP of 60 mm Hg; Group II (nine animals) was resuscitated to a goal MAP of 80 mm Hg; and Group III (control; six animals) was not resuscitated. After 60 minutes, the aortic hemorrhage was controlled and the animals were resuscitated to baseline physiological parameters and observed for 150 minutes. Mortality rates were 11%, 50%, and 100% for Groups I, II, and III, respectively (Fisher's exact test; p = 0.002). The total hemorrhage volume was greater in Group II (69+/-32 ml/kg), as compared with Group I (41+/-18 ml/kg) and Group III (37+/-3 ml/kg) according to analysis of variance (p < 0.05). In surviving animals, cerebral perfusion pressure, cerebral blood flow (CBF), cerebral venous O2 saturation (ScvO2), and cerebral metabolic rate of O2 did not differ among groups. Although CBF was approximately 50% of baseline during the period of limited resuscitation in Group I, ScvO2 remained greater than 60%, and arteriovenous O2 differences remained within normal limits. In this model of FPI and uncontrolled hemorrhage, early aggressive resuscitation, which is currently recommended, resulted in increased hemorrhage and failure to optimize cerebrovascular parameters. In addition, a 60-minute period of moderate hypotension (MAP = 60 mm Hg) was well tolerated and did not compromise cerebrovascular hemodynamics, as evidenced by physiological parameters that remained within the limits of cerebral autoregulation.

The veterinary experience

Veterinarians have three decades of experience with the use of α2-agonists. Xylazine, synthesized in 1962, was the first α2-agonist to be used as a sedative and analgesic, first in cattle and later in many other species. The major side-effects were bradycardia and a biphasic blood pressure response with moderate hypotension following an initial hypertensive episode. In the 1980s, new α2-agonists with a much higher potency and greater specificity at central α2-adrenoceptor sites were introduced: detomidine, romifidine and medetomidine. These drugs showed side-effects similar to those of xylazine but had a longer sedative and analgesic action. Alpha2-agonists have proved to be safe agents for analgo-sedation and muscle relaxation in healthy animals. In combination with opioids or mono-anaesthetics, they can be used either to induce a profound sedative-analgesic state or to enhance general anaesthesia while reducing the anaesthetic requirement and smoothing the recovery phase. The availability of α2-antagonists such as atipamezole has increased safety and allowed remarkable versatility in veterinary anaesthetic management.

Moderate controlled hypotension with sodium nitroprusside does not improve surgical conditions or decrease blood loss in endoscopic sinus surgery

Study Objective: To determine if moderate controlled hypotension can improve the dryness of the surgical field in endoscopic sinus surgery. Study Design: Randomized, prospective study. Setting: University-affiliated hospital. Patients: 32 ASA physical status I and II adult patients undergoing endoscopic sinus surgery. Interventions: All patients were premedicated orally with chlorazepate. Patients in Group H received 12.5 mg captopril orally prior to surgery. Anesthesia was provided using an intravenous (IV) technique supplemented with nitrous oxide (N 2O); anesthesia was maintained with boluses of 2 μg/kg fentanyl and a propofol infusion at rates between 3 and 9 mg/kg/h at the discretion of the anesthetist. In Group H, sodium nitroprusside was infused at a rate of 1 to 2.5 μg/kg/min to maintain moderate controlled hypotension with mean blood pressure of 65 to 75 mm Hg. Measurements and Main Results: Arterial blood pressure was assessed via the radial artery. Readings were recorded prior to intubation, immediately after intubation, at the start of surgery, then at 5, 15, 30, 45, and 60 minutes intraoperatively, and at the end of surgery. Intraoperative blood loss, dryness of the surgical field, adrenocorticotropic (ACTH) hormone, arginin-vasopressin (AVP), cortisol, and the preoperative and postoperative psychomotoric function were examined. At the start of surgery and thereafter, MAP increased in Group N but not in Group H. Throughout surgery, MAP was significantly lower in Group H than in Group N. Blood loss, dryness of the surgical field, ACTH, AVP, and cortisol levels, and psychomotoric function were not significantly different between the groups. Conclusion: Intravenous anesthesia supplemented with N 2 is as effective as moderate controlled hypotension when blood loss, visibility in the surgical field, ACTH, AVP, and cortisol are examined.

Impaired cerebral autoregulation 24 h after induction of transient unilateral focal ischaemia in the rat.

Cerebral blood flow (CBF) and cerebral autoregulation have been investigated 24 h after transient focal ischaemia in the rat. Cerebral blood flow was measured autoradiographically before and during a moderate hypotensive challenge, to test autoregulatory responses, using two CBF tracers, (99m)Tc-d,l-hexamethylproyleneamine oxide and 14C-iodoantipyrine. Prior to induced hypotension, CBF was significantly reduced within areas of infarction; cortex (28 +/- 20 compared with 109 +/- 23 mL/100 g/min contralateral to ischaemic focus, P = 0.001) and caudate (57 +/- 31 compared with 141 +/- 32 mL/100 g/min contralaterally, P = 0.005). The hypotensive challenge (mean arterial pressure reduced to 60 mmHg by increasing halothane concentration) did not compromise grey matter autoregulation in the contralateral hemisphere; CBF data were not significantly different at normotension and during hypotension. However, in the ipsilateral hemisphere, a significant volume of cortex adjacent to the infarct, which exhibited normal flow at normotension, became oligaemic during the hypotensive challenge (e.g. frontal parietal cortex 109 +/- 15% to 65 +/- 15% of cerebellar flow, P < 0.01). This resulted in a 2.5-fold increase in the volume of cortex which fell below 50% cerebellar flow (39 +/- 34 to 97 +/- 46 mm3, P = 0.003). Moderate hypotension induced a significant reduction in CBF in both ipsilateral and contralateral subcortical white matter (P < 0.01). In peri-infarct caudate tissue, CBF was not significantly affected by hypotension. In conclusion, a significant volume of histologically normal cortex within the middle cerebral artery territory was found to have essentially normal levels of CBF but impaired autoregulatory function at 24 h post-ischaemia.

Heart function after severe hemorrhagic shock.

Test whether brief deep hemorrhagic hypotension or prolonged moderate hemorrhagic hypotension impairs intrinsic heart function. Pentobarbital-anesthetized, non-anticoagulated rats were cannulated via the carotid artery. This study focuses on three main groups: 1) hemorrhage to a mean arterial blood pressure (MAP)=25 mm Hg for 1 h (1 h severe shock), 2) hemorrhage to MAP=40 mm Hg for 3 h (3 h moderate shock), 3) no hemorrhage (control). Hearts were either freeze-clamped in-situ for tissue analysis (n=6 per group) or were removed to study in vitro cardiac function and efficiency using a working heart perfusion (n=12 per group, glucose (11 mM)/palmitate (0.4 mM), 3% BSA buffer). Following perfusion, hearts were freeze-clamped and analyzed for free CoA, acetyl-, succinyl-, and malonyl-CoA, ATP content and for TNF-alpha content. Isolated working hearts obtained following 1 h of severe shock generated 20% less hydraulic work than hearts obtained from control rats or rats subjected to 3 h of moderate shock. The cardiac efficiency (work/O2 consumption) was also significantly reduced with 1 h severe shock (0.76 +/- 0.07 after 15 min perfusion) versus control (0.96 +/- 0.06) or 3 h prolonged shock (1.10 +/- 0.09). Myocardial Co-A ester, ATP and TNF-alpha concentrations were not different between control and shocked hearts, although TNF-alpha concentrations increased significantly in all hearts during ex vivo perfusion. Depth of hypotension is more important than duration in causing intrinsic cardiac dysfunction. This post-hemorrhagic cardiac dysfunction is not a result of substrate limitation to the heart, nor myocardial TNF-alpha accumulation, but is more likely a result of impaired transfer of energy from molecular oxygen into external cardiac work.

Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension.

It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). Induction of hypothermia occurred at 15 min postinjury, to a level of 30 degrees C for 60 min. At the designated time points (4 and 24 h), the animals were sacrificed via standard transcardial perfusion techniques for histological processing. Quantitative assessment of neuronal damage using routine H&E staining at 4 hours showed neuronal damage which correlated with the severity of secondary insult. Animals exposed to trauma alone had a mean number of damaged neurons of 7.61 +/- 3.08/high powered field (hpf) compared with a mean of 1.21 +/- 0.30/hpf in the sham operated group (p = 0.015). Animals exposed to trauma with 10 min of hypoxia and hypotension (THH-10) showed a statistically significant number of damaged neurons compared to the sham-operated animals (7.50 +/- 2.15 damaged neurons/hpf, p = 0.013), whereas, neuronal damage in animals undergoing trauma with a 30-min secondary insult of hypoxia and hypotension (THH-30) was markedly increased (100 +/- 30.20/hpf, p = 0.002). Statistical analysis showed no significant difference in neuronal damage in animals subjected to secondary insult alone. At 24 h, the evolution of neuronal damage in the trauma alone group (5.08 +/- 1.63/hpf) was relatively static; however, there was a remarkable increase in the neuronal damage of the THH-10 group (29.88 50 +/- 8.20/hpf). However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.

Pharmacokinetics and efficacy of epidurally delivered sustained-release encapsulated morphine in dogs.

We evaluated the epidural effects of a multivesicular liposome-based sustained-release preparation of morphine (C0401) on behavior and lumbar cerebrospinal fluid and serum kinetics of morphine. Beagle dogs were prepared with lumbar epidural catheters with subcutaneous injection ports and lumbar intrathecal catheters. Each dog (n = 6) received the following by the epidural route: 5 mg/3 ml morphine sulfate in saline (MS-5), 10 mg/3 ml C0401 (C0401-10), and 30 mg/3 ml C0401 (C0401-30). Behavioral and physiologic parameters and nociceptive responses (skin twitch latency) were evaluated, and morphine concentrations were determined in lumbar cerebrospinal fluid and serum. All morphine treatments blocked the skin twitch response. Time to onset was 1.3 +/- 0.3 h for C0401-30; 2.6 +/- 0.6 h for C0401-10; and 0.4 +/- 0.2 h for MS-5. Duration of action was 62 +/- 0.3 h for C0401-30; 27 +/- 2 h for MS-5. All treatments produced a modest reduction in arousal, muscle tone, and coordination, with the duration of the C0401-30 preparation being longer lasting. Respiratory rate was mildly depressed by all treatments, and moderate hypotension was noted. Time to peak cerebrospinal fluid morphine concentration was 11 h for C0401-30; 3 h for C0401-10; and 5 min for MS-5. Peak lumbar cerebrospinal fluid level was 34,992 +/- 5,578 ng/ml for MS-5; 14,483 +/- 3,438 ng/ml for C0401-30; and 10,730 +/- 2,888 ng/ml for C0401-10. Morphine mean residence time in lumbar cerebrospinal fluid was 0.8 +/- 0.1 h for MS-5; 8.9 +/- 1.0 h for C0401-30. Kinetics studies showed that multivesicular liposome sequestration results in a restrained and persistent release of morphine from the epidural space. This extended release corresponded with an extended duration of analgesia without an attendant increase in the incidence of side effects.

Mechanism of adrenal insufficiency following trauma and severe hemorrhage: role of hepatic 11beta-hydroxysteroid dehydrogenase.

Although adrenal insufficiency may not occur with moderate hypotension, it does occur with severe hemorrhage. Since hepatocellular function is depressed following severe hemorrhage, it remains unknown whether the liver plays any role in regulating adrenal function after trauma and hemorrhagic shock. Hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD), a microsomal enzyme responsible for the degradation of bioactive corticosterone, plays a major role in the development of adrenal insufficiency following trauma and severe hemorrhage. Male rats underwent laparotomy to induce trauma before hemorrhage. They were then bled to and maintained at a blood pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate. The rats were then resuscitated with 4 times the volume of maximal bleed-out with Ringer lactate during a 60-minute period. Plasma levels of corticosterone and corticotropin were measured at various intervals. In additional groups, corticotropin-induced corticosterone release, adrenal contents of corticosterone and cyclic adenosine monophosphate (cAMP), hepatic 11beta-HSD activity, and plasma levels of corticosterone-binding globulin were determined at 1.5 hours after resuscitation. Moreover, a model of moderate hypotension (blood pressure, 80 mm Hg) was used to determine whether adrenal function is depressed under such conditions. At the time of maximal bleed-out, plasma corticosterone and corticotropin levels increased by 245% (P<.001) and 293% (P<.001), respectively. Despite corticotropin levels being similar to those of the animals undergoing sham operation after resuscitation, corticosterone levels in hemorrhaged animals remained elevated up to 4 hours after resuscitation (by 158%-207%; P<.001). In addition, corticotropin-induced corticosterone release decreased by 78% at 1.5 hours after resuscitation (P = .009). In contrast, moderate hypotension did not reduce corticotropin-induced corticosterone release. Adrenal corticosterone content and cAMP levels (i.e., the second messenger of corticotropin action) decreased by 55% (P<.001) and 25% (P = .03), respectively. Hepatic 11beta-HSD activity decreased significantly at 1.5 hours after resuscitation (P<.001). Sustained increase in plasma corticosterone levels following hemorrhage and resuscitation may be, in part, due to the decreased hepatic 11beta-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhage.

Distribution of neurons projecting to the rostral ventrolateral medullary pressor region that are activated by sustained hypotension

Hypotension produces a reflex increase in the activity of sympathetic vasomotor and cardiac nerves. It is believed that the reflex sympathoexcitation is due largely to disinhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla, but it is possible that it may also be mediated by excitatory inputs from interneurons that are activated by a fall in blood pressure. The aim of this study in conscious rabbits was to identify and map neurons with properties that are characteristic of interneurons conveying excitatory inputs to the rostral ventrolateral medullary pressor region in response to hypotension. In a preliminary operation, a retrogradely-transported tracer, fluorescent-labelled microspheres, was injected into the functionally-identified pressor region in the rostral ventrolateral medulla. After a waiting period of at least one week, a moderate hypotension (decrease in arterial pressure of approximately 20 mmHg) was induced in conscious rabbits for 60 min by the continuous infusion of sodium nitroprusside. In confirmation of a previous study from our laboratory, [Li and Dampney (1994) Neuroscience 61, 613–634] hypotension resulted in the expression of Fos (the protein product of c- fos, a marker of neuronal activation) in many neurons in several distinct regions in the brainstem and hypothalamus. Some of these regions (nucleus tractus solitarius, area postrema, caudal and intermediate ventrolateral medulla, parabrachial complex in the pons, and paraventricular nucleus in the hypothalamus) also contained large numbers of retrogradely-labelled cells. Approximately 10% of the Fos-positive neurons in the nucleus tractus solitarius, and 15–20% of Fos-positive neurons in the caudal and intermediate ventrolateral medulla were also retrogradely-labelled from the rostral ventrolateral medullary pressor region. In other brain regions, very few double-labelled neurons were found. In previous studies from our laboratory, we have determined the distribution of neurons in the brainstem that project to the rostral ventrolateral medullary pressor region and that are also activated by hypertension [Polson et al. (1995) Neuroscience 67, 107–123] or by hypoxia. [Hirooka et al. (1997) Neuroscience 80, 1209–1224] Comparison of the present results with those from these previous studies indicate that although hypotension and hypoxia both elicit powerful reflex sympathoexcitatory responses, the central pathways subserving these effects in conscious animals are fundamentally different. Hypoxia activates rostral ventrolateral medullary sympathoexcitatory neurons mainly via a major direct excitatory projection from the nucleus tractus solitarius, as well as from the Kölliker–Fuse nucleus in the pons, while in contrast the activation of these neurons in response to hypotension appears to be due mainly to disinhibition, mediated via inhibitory interneurons. In addition, however, inputs originating from excitatory interneurons in the nucleus tractus solitarius and caudal and intermediate parts of the ventrolateral medulla appear to contribute to the hypotension-evoked activation of sympathoexcitatory neurons in the rostral ventrolateral medulla.

Multimodal strategy for reduction of homologous transfusions in cranio-maxillofacial surgery

The transfusion of homologous blood carries well-known risks that have prompted efforts to develop alternative techniques. Such measures are of particular interest to patients undergoing elective procedures. A total of 204 patients, out of 1470 patients who consecutively underwent major cranio-maxillofacial procedures under general anesthesia over a two-year period, were enrolled in a prospective protocol to reduce homologous transfusion requirements when a blood loss in excess of 500 ml was anticipated. The data were compared with the results of a retrospective control group ( n-2890) covering major procedures during the previous four years, when blood-saving measures were applied occasionally, but not based on a global strategy. Techniques for the reduction of homologous transfusions were acute normovolemic hemodilution, controlled moderate hypotension, cell saver and predeposit autologous blood. In addition, preoperative administration of human recombinant erythropoietin was introduced during the last year of the study. These techniques were applied individually or in combination, depending on contraindications specific for each technique, using invasive monitoring in order to maintain intraoperative hemodynamic stability. The goal of this study was to examine the extent to which homologous transfusions may be reduced with the systematic application of transfusion-sparing techniques. Of 204 patients qualifying for the transfusion-sparing protocol, 30 received homologous transfusions. In comparison to the control group, utilization of transfusion-sparing techniques had doubled. The overall reduction in the use of homologous transfusions was highly significant. When acute normovolemic hemodilution, controlled moderate hypotension and the cell saver were used in combination, a greater reduction in homologous transfusions was achieved than with the use of either a single modality or combination of any two. No transfusions were required in patients pretreated with erythropoietin.

Autoregulation of cerebral blood flow and brain lesions in newborn infants

These speculations received support from the discovery of proportionality between arterial blood pressure and cerebral blood flow in newborn babies whose clinical condition was unstable. 6 Protective autoregulation of blood flow is one physiological regulatory mechanism that may be disturbed. It maintains constant blood flow over wide ranges of perfusion pressures by arteriolar vasodilation when there is moderate hypotension and by arterolar constriction when there is raised arterial blood pressure. The autoregulatory response is probably a final common pathway for several mechanical, metabolic, and neurogenic processes. It may be abolished by several mechanisms. One is perinatal hypoxia. Studies in fetal and newborn lambs suggest that oxygen saturation at 50% for longer than 10 min results in global abolition of autoregulation for several hours. 7,8 Thus impaired gas exchange across the placenta (eg, in abruption or chorioamnionitis), or across alveoli (eg, in respiratory distress syndrome) are common causes of loss of autoregulation in neonates. Autoregulation seems to be more vulnerable than other regulatory mechanisms for the cerebral circulation. 9

Cerebrovascular effects of high intracranial pressure after moderate hemorrhage.

Patients with head injuries often develop increased intracranial pressure after hemorrhage. The authors studied the effect of moderate hemorrhage followed by elevated intracranial pressure on cerebrovascular variables. Cerebral blood flow in 13 pigs was measured with laser Doppler flowmetry, and cerebral venous blood gases were taken from the sagittal sinus. High intracranial pressure (80% of mean arterial pressure) was induced by infusion of artificial cerebrospinal fluid into the cisterna magna, and blood pressure was reduced by bleeding to a mean of 78% of the prebleeding values in eight pigs. Five pigs served as secondary controls. High intracranial pressure before hemorrhage caused a decrease in cerebral blood flow to 34% of the baseline values, a decrease in sagittal sinus oxygen saturation to 46%, and a decrease in cerebral perfusion pressure to 36%, but did not change cerebrovascular resistance. High intracranial pressure after hemorrhage decreased cerebral blood flow to 14% of baseline values. Sagittal sinus oxygen saturation decreased to 22%, cerebral perfusion pressure decreased to 30%, and the cerebrovascular resistance increased by 355%. The moderate hypotension after hemorrhage caused a considerable enhancement of the effects of high intracranial pressure on cerebral hemodynamics.

Evaluation of the ratio of cerebral blood flow to cerebral blood volume as an index of local cerebral perfusion pressure.

Local cerebral perfusion pressure (CPP), a crucial parameter that should allow a better assessment of the haemodynamic compromise in cerebrovascular diseases, is not currently measurable by non-invasive means. Experimental and clinical studies have suggested that the regional ratio of cerebral blood flow to cerebral blood volume (CBF:CBV), as measured by PET, represents an index of local CPP in focal ischaemia. The present study was designed to evaluate further the reliability of the CBF:CBV ratio during manipulations of CPP by deliberately varying mean arterial pressure (MAP) in the anaesthetized baboon. Cortical CBF, CBV, cerebral metabolic rate for oxygen (CMRO2) and oxygen extraction fraction were measured by PET using the (15)O steady-state technique in 10 anaesthetized baboons. Five baboons (Group A) underwent four PET examinations at different levels of MAP: base line (101 +/- 6 mmHg) followed by moderate hypotension (58 +/- 3 mmHg) and, in a separate experiment, minor hypotension (72 +/- 3 mmHg) followed by profound hypotension (34 +/- 5 mmHg). Trimetaphan was used to lower MAP to minor and moderate levels while profound hypotension was achieved by the combined effects of trimetaphan and lower-body negative pressure. Five other baboons (Group B) were subjected to hypertension (121 +/- 2 mmHg) induced by metaraminol and were compared with their base line state (81 +/- 10 mmHg). While CBF displayed significant changes with varying MAP, i.e. decrease and increase with hypotension and hypertension, respectively (-11% from base line to moderate hypotension compared with -20%, from minor to profound hypotension and +31% from base line to hypertension), CBV was more variable and did not significantly change, except with profound hypotension when the increase was significant (+13%). The CBF:CBV ratio decreased significantly at all stages of hypotension (-21 and -31%) and was significantly increased during hypertension (+30%). Importantly, the CBF:CBV ratio demonstrated a significant correlation with MAP (rho = 0.78, Spearman's rank correlation coefficient, P < 0.01). No major changes in CMRO2 were noted during either hypotension or hypertension. Our results demonstrate that, under physiological conditions, cortical CBF:CBV is significantly correlated with CPP, itself a function of MAP. In the investigated range of MAP, the relationships between CBF:CBV and MAP appear to be linear. These findings further argue for the reliability of CBF:CBV as an index of CPP in situations where increases or decreases of MAP without superimposed changes in cerebrovascular tone are encountered, and they confirm the potential usefulness of this regional ratio for clinical investigations and management in cerebrovascular diseases.

Pharmacological analysis of the haemodynamic effects of 5-HT1B/D receptor agonists in the normotensive rat.

1 The receptors involved in mediating the haemodynamic effects of three 5-HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg kg(-1); each dose over 5 min) induced dose-dependent and marked hypotension (-42+/-6 and -34+/-4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5+/-3 mmHg) and bradycardia (-85+/-16 and -44+/-12 beats min(-1) at the highest dose, respectively; both P<0.05 vs vehicle: +16+/-6 beats min(-1)). Zolmitriptan evoked only moderate hypotension at the highest dose (-19+/-9 mmHg; P<0.05 vs vehicle). 3 A high dose of the 5-HT1B/D receptor antagonist, GR 127935 (0.63 mg kg(-1), i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (-35+/-6 mmHg and -52+/-19 beats min(-1), respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (-20+/-5 mmHg and -30+/-17 beats min(-1), respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats). 4 The selective 5-HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg(-1), i.v.), dose-dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (-4+/-3 mmHg and -15+/-8 beats min(-1); both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (-13+/-4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle). 5 In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5+/-4 mmHg and -6+/-16 beats min(-1), respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5+/-6 beats min(-1); not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (-9+/-9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats). 6 In bilaterally vagotomized and atropine-treated (1 mg kg(-1), i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-31+/-4 mmHg and -64+/-9 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (-47+/-8 mmHg and -56+/-10 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. 7 In conclusion, the 5-HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT1A receptors, and a consequent reduction in sympathetic outflow.

Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo.

Vascular expression and cellular functions of the thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) suggest similar but distinct vascular regulatory roles. The vascular actions of PAR-1 and PAR-2 in vivo were differentiated by monitoring mean arterial pressure (MAP) and heart rate (HR) of anesthetized mice in response to intravenous SFLLRN (0.1, 0.3, and 1 mumol/kg) and SLIGRL (0.1, 0.3, and 1 mumol/kg), the respective receptor-activating sequences for PAR-1 and PAR-2, and TFLLRNPNDK (0.3, 1, and 3 mumol/kg), a synthetic peptide selective for PAR-1. All peptides dose dependently decreased MAP (order of potency: SLIGRL > SFLLRN > TFLLRNPNDK). SLIGRL induced a more prolonged hypotension with a slow return to baseline, whereas SFLLRN- and TFLLRNPNDK-induced hypotension was followed by a rapid return towards baseline and a sustained moderate hypotension. SFLLRN and TFLLRNPNDK, but not SLIGRL, decreased HR. N omega-Nitro-L-arginine methyl ester HCl (L-NAME), an inhibitor of nitric oxide synthesis, attenuated the cumulative hypotensive response to SLIGRL but had no effect on the SFLLRN and TFLLRNPNDK hypotension. However, L-NAME revealed a rebound hypertension in response to SFLLRN and TFLLRNPNDK but not SLIGRL. In conclusion, activation of either PAR-1 or PAR-2 in vivo results in hypotension. In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction. Thus, these different hemodynamic responses in vivo suggest distinct physiological or pathophysiological roles for PAR-1 and PAR-2 in local vascular regulation.

Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo

Vascular expression and cellular functions of the thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) suggest similar but distinct vascular regulatory roles. The vascular actions of PAR-1 and PAR-2 in vivo were differentiated by monitoring mean arterial pressure (MAP) and heart rate (HR) of anesthetized mice in response to intravenous SFLLRN (0.1, 0.3, and 1 µmol/kg) and SLIGRL (0.1, 0.3, and 1 µmol/kg), the respective receptor-activating sequences for PAR-1 and PAR-2, and TFLLRNPNDK (0.3, 1, and 3 µmol/kg), a synthetic peptide selective for PAR-1. All peptides dose dependently decreased MAP (order of potency: SLIGRL &gt;&gt; SFLLRN &gt;&gt; TFLLRNPNDK). SLIGRL induced a more prolonged hypotension with a slow return to baseline, whereas SFLLRN- and TFLLRNPNDK-induced hypotension was followed by a rapid return towards baseline and a sustained moderate hypotension. SFLLRN and TFLLRNPNDK, but not SLIGRL, decreased HR. Nomega-Nitro-L-arginine methyl ester HCl (L-NAME), an inhibitor of nitric oxide synthesis, attenuated the cumulative hypotensive response to SLIGRL but had no effect on the SFLLRN and TFLLRNPNDK hypotension. However, L-NAME revealed a rebound hypertension in response to SFLLRN and TFLLRNPNDK but not SLIGRL. In conclusion, activation of either PAR-1 or PAR-2 in vivo results in hypotension. In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction. Thus, these different hemodynamic responses in vivo suggest distinct physiological or pathophysiological roles for PAR-1 and PAR-2 in local vascular regulation.Key words: protease activated receptor, thrombin receptor, protease activated receptor 2 (PAR-2), arterial pressure.