Blood Pressure and the Brain: How Low Can You Go?

There are occasionally intraoperative circumstances in which reduction of mean arterial pressure (MAP) to levels well below those that occur in nonanesthetized adults is necessary or unavoidable. In these situations, clinicians are inevitably concerned about the limits of the tolerance of the brain for hypotension. Reference to the phenomenon of cerebral blood flow autoregulation is frequently made in discussions of safe MAP limits. However, in several respects, prevalent conceptions about cerebral blood flow autoregulation may be incomplete or inaccurate. The principal theses offered by this review are: (1) that the average lower limit of cerebral blood flow autoregulation in normotensive adult humans is not less than a MAP of 70 mm Hg; (2) that there is considerable intersubject variability in both the lower limit of cerebral blood flow autoregulation and the efficiency of cerebral blood flow autoregulation; (3) that there is a substantial blood flow reserve that buffers the normal central nervous system against critical blood flow reduction in the face of hypotension; (4) that there are several common clinical phenomena that have the potential to compromise that buffer, and that should be taken into account in decision making about minimum acceptable MAPs; and (5) that the average threshold for the onset of central nervous system ischemic symptoms is probably a MAP of 40-50 mm Hg at the level of the circle of Willis in a normotensive adult in a vertical posture and 45-55 mm Hg in a supine subject. However, these MAPs should probably only be approached deliberately when the exigencies of the surgical situation absolutely require it.

Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

Statins, which reduce LDL-cholesterol by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin-induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity-dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2T202/Y204, AktSer473, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor, and insulin receptor-ß; decreased Ras homolog gene family member A activation; and induced apoptosis. In cardiomyocyte-equivalent HL-1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long-term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size-variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria- and endoplasmic reticulum-related genes; and a 21% increase in mortality in cardiac-specific vinculin-knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long-term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications.-Godoy, J. C., Niesman, I. R., Busija, A. R., Kassan, A., Schilling, J. M., Schwarz, A., Alvarez, E. A., Dalton, N. D., Drummond, J. C., Roth, D. M., Kararigas, G., Patel, H. H., Zemljic-Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

Baseline Cerebral Metabolic Rate Is a Critical Determinant of the Cerebral Vasodilating Potency of Volatile Anesthetic Agents.

A Comparison of the Direct Cerebral Vasodilating Potencies of Halothane and Isoflurane in the New Zealand White Rabbit. By Drummond JC, Todd MM, Scheller MS, and Shapiro HM. ANESTHESIOLOGY 1986; 65:462-7. Reprinted with permission.Halothane is commonly viewed as a more potent cerebral vasodilator than isoflurane. It was speculated that the lesser vasodilation caused by isoflurane might be the result of the greater reduction in cerebral metabolic rate (CMR) that it causes, and that the relative vasodilating potencies of halothane and isoflurane would be similar if the two agents were administered in a situation that precluded volatile-agent-induced depression of CMR. To test this hypothesis, cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRO2) were measured in two groups of rabbits before and after the administration of 0.75 MAC halothane or isoflurane. One group received a background anesthetic of morphine and N2O, which resulted in an initial CMRO2 of 3.21 ± 0.17 (SEM) ml · 100 g · min; second group received a background anesthetic of high-dose pentobarbital, which resulted in an initial CMRO2 of 1.76 ± 0.16 ml · 100 g · min. In rabbits receiving a background of morphine sulfate/N2O, halothane resulted in a significantly greater CBF (65 ± 10 ml · 100 g · min) than did isoflurane (40 ± 5 ml · 100 g · min). Both agents caused a reduction in CMRO2, but CMRO2 was significantly less during isoflurane administration. By contrast, with a background of pentobarbital anesthesia, CBF increased by significant and similar amounts with both halothane and isoflurane. With halothane, CBF increased from 22 ± 2 ml · 100 g · min in the control stage to 39 ± 3, and with isoflurane from 24 ± to 38 ± 2 ml · 100 g · min. CMRO2 was not depressed further by either halothane or isoflurane. These results suggest that the relative effects of halothane and isoflurane on CBF are dependent on the CMR present prior to their administration. When the preexistent CMR is not markedly depressed, isoflurane decreases CMR and causes less cerebral vasodilation than does halothane. When initial CMR is depressed, halothane and isoflurane have similar vasodilating potencies.

The Inter-Mammary Sticky Roll: A Novel Technique for Securing a Doppler Ultrasonic Probe to the Precordium for Venous Air Embolism Detection.

Venous air embolism is a devastating and potentially life-threatening complication that can occur during neurosurgical procedures. We report the development and use of the "inter-mammary sticky roll," a technique to reliably secure a precordial Doppler ultrasonic probe to the chest wall during neurosurgical cases that require lateral decubitus positioning. We have found that this noninvasive technique is safe, and effectively facilitates a constant Doppler signal with no additional risk to the patient.

The Effect of Clevidipine on Cerebral Blood Flow Velocity and Carbon Dioxide Reactivity in Human Volunteers.

BACKGROUND: Clevidipine is a short acting, esterase metabolized, calcium channel antagonist administered as a continuous infusion for control of hypertension. Its profile allows for rapid titration and may be uniquely suited to achieving tight hemodynamic targets in neurosurgical and neurocritical care patients. The present study was designed to investigate the effect of clevidipine infusion on cerebral blood flow and cerebral CO2 responsiveness as measured by cerebral blood flow velocity (CBFV) using transcranial Doppler. MATERIALS AND METHODS: CBFV was continuously recorded in 5 healthy subjects during the following conditions: baseline 1 (BL1); baseline with hyperventilation (HV1); baseline 2 (BL2); clevidipine infusion to achieve 15% mean arterial pressure (MAP) reduction (C15); clevidipine infusion to achieve 30% MAP reduction (C30); clevidipine infusion to 30% MAP reduction with hyperventilation (HV2). RESULTS: The mean CBFV during intermediate (C15) or maximum (C30) dose clevidipine infusion was unchanged compared with baseline (BL2) (F2,8=0.66; P=0.54). Cerebral CO2 reactivity, expressed as %[INCREMENT]CBFV/[INCREMENT]mm Hg CO2, was not significantly different in the presence of maximal-dose clevidipine (HV2) as compared with baseline (HV1) (1.6±0.4 vs. 1.6±0.3%[INCREMENT]CBFV/[INCREMENT]mm Hg CO2, P=0.73). CONCLUSIONS: Clevidipine infusion did not significantly increase CBFV nor was cerebral CO2 reactivity reduced during maximal-dose clevidipine infusion. Further systematic investigation of clevidipine in patients with central nervous system pathology seems justified.

An Observational Study of Cerebral Blood Flow Velocity During Hypotensive Epidural Anesthesia.

BACKGROUND: Hypotensive epidural anesthesia (HEA), as practiced at our institution, uses sympathetic blockade to achieve mean arterial blood pressure (MAP) of ≤50 mm Hg while administering epinephrine by infusion to support the circulation. HEA has not been associated with gross adverse effects on neurologic outcome or cognitive function in the postoperative period, suggesting adequate cerebral blood flow (CBF). However, the use of MAPs well below the commonly accepted lower limit of CBF autoregulation suggests that CBF should be significantly reduced below normal levels. To examine these conflicting hypotheses, we performed a prospective investigation of the effects of HEA on CBF velocity (CBFV), an accepted index of cerebral perfusion. METHODS: Fifty-two hip replacement patients were studied. HEA was induced by lumbar epidural injection of local anesthetic and infusion of epinephrine to achieve an MAP of ≤50 mm Hg. Propofol/midazolam sedation was administered. Baseline CBFV was recorded pre-HEA (after sedation and before local anesthetic injection) and continuously thereafter. RESULTS: During HEA, MAP decreased by 40% and was stable throughout. The CBFVmean at baseline and at 3 HEA intervals during surgery was 46 ± 12 (SD), 45 ± 12, 47 ± 14, and 47 ± 14 cm·s, respectively. Although mean CBFVmean did not vary, there was considerable heterogeneity among patients. Twelve patients (23%) experienced reductions of CBFVmean of >20% during HEA intervals (99% lower confidence limit: 9%) and 6 (12%) reductions of >30% (99% lower confidence limit: 1%). There was no correlation between CBFVmean and MAP for MAPs between 100 and 40 mm Hg (R = 0.0015, P = 0.44). There were no instances of gross postoperative neurologic injury. CONCLUSIONS: Both hypotheses proved partially correct. CBFV was sometimes well maintained during HEA, despite MAPs well below the commonly accepted lower limit of autoregulation. However, there was considerable interindividual heterogeneity with 23% of subjects having CBFV reductions >20% (99% lower confidence limit: 9%), with some reductions approaching the threshold for ischemic injury. The present data do not allow us to determine whether hypotension would be similarly tolerated in other circumstances.

Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis.

PURPOSE: We describe an instance in which complete paraplegia was evident immediately postoperatively after apparently uneventful lumbar epidural-general anesthesia in a patient with Morquio Type A syndrome (Morquio A) with moderate thoracic spinal stenosis. CLINICAL FEATURES: A 16-yr-old male with Morquio A received lumbar epidural-general anesthesia for bilateral distal femoral osteotomies. Preoperative imaging had revealed a stable cervical spine and moderate thoracic spinal stenosis with a mild degree of spinal cord compression. Systolic blood pressure (BP) was maintained within 20% of the pre-anesthetic baseline value. The patient sustained a severe thoracic spinal cord infarction. The epidural anesthetic contributed to considerable delay in the recognition of the diagnosis of paraplegia. CONCLUSION: This experience leads us to suggest that, in patients with Morquio A, it may be prudent to avoid the use of epidural anesthesia without very firm indication, to support BP at or near baseline levels in the presence of even moderate spinal stenosis, and to avoid flexion or extension of the spinal column in intraoperative positioning. If the spinal cord/column status is unknown or if the patient is known to have any degree of spinal stenosis, we suggest that the same rigorous BP support practices that are typically applied in other patients with severe spinal stenosis, especially stenosis with myelomalacia, should apply to patients with Morquio A and that spinal cord neurophysiological monitoring should be employed. In the event that cord imaging is not available, e.g., emergency procedures, it would be prudent to assume the presence of spinal stenosis.

Direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia.

PURPOSE: When positioning patients with meningocele and meningomyelocele, it is standard practice to avoid direct pressure on the lesions. That caution is intended to prevent injury to neural elements within the lesion and violation of the cerebrospinal fluid space. We herein report an additional hazard of direct intraoperative pressure on such lesions. An adult patient with a lumbosacral pseudomeningocele sustained a cerebral ischemic injury as a consequence of direct pressure on the lesion during general anesthesia. CLINICAL FEATURES: A 32-yr-old male with spina bifida and a pseudomeningocele related to recent lumbar surgery underwent a urologic procedure in the lithotomy position. Because the lesion was recognized to lie to the left of the midline, cushioning was placed under the patient's left hip and buttock. The patient was slow to awaken and has sustained significant long-term cognitive deficits. Imaging is consistent with a diffuse cerebral ischemic insult. CONCLUSION: In retrospect, the size and leftward extent of the pseudomeningocele were not appreciated preoperatively, and in spite of the care taken, intraoperative pressure was placed on the lesion. This report cautions that intraoperative pressure related to positioning patients with extra-axial lesions containing cerebrospinal fluid (CSF), e.g., meningoceles and pseudomeningoceles, can result in increases in CSF pressure and thereby a reduction in cerebral perfusion pressure sufficient to result in cerebral ischemia.

Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry.

Membrane/lipid rafts (MLR) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis of mevalonic, a precursor to cholesterol via the mevalonate pathway. Because there has been controversy over the effects of statins on neuronal and cognitive function, we investigated the impact of long-term atorvastatin treatment (5mg/kg/d for 7 months by oral gavage) on behavior, cognition, and brain biochemistry in mice. We hypothesized that long-term statin treatment would alter lipid rafts and cognitive function. Atorvastatin treatment resulted in behavioral deficits as measured in paradigms for basic exploration (open field activity) and cognitive function (Barnes maze, startle response) without impairment in global motor function (Rotor Rod). Furthermore, significant changes in MLR-associated proteins (syntaxin-1α and synaptophysin) and a global change of post-synaptic density protein-95 (PSD95) were observed. The observed decreases in the MLR-localized pre-synaptic vesicle proteins syntaxin-1α and synaptophysin suggest a molecular mechanism for the statin-associated impairment of cognitive function that was observed and that has been suggested by the clinical literature.