John C. Drummond

Monitoring depth of anesthesia: with emphasis on the application of the bispectral index and the middle latency auditory evoked response to the prevention of recall.

AMONG the earliest systematic observations of the physiologic effects of anesthetic agents was John Snow’s description, in 1847, of the various stages of ether anesthesia. Although the focus has evolved somewhat, our interest in measures of the depth of anesthesia has persisted. Although the concern was initially largely one of avoiding the hazards of overdose, we have added a greater interest in the prevention of “underdosage.” There is considerable interest in preventing potentially hazardous hemodynamic and movement responses and in preventing recall. The latter concern applies most particularly to the patient who has received neuromuscular blocking agents. The contemporary literature also indicates an interest in using depth of anesthesia monitors as a means of controlling cost. The hope is that precise titration of anesthetic agents, as guided by a monitor of anesthetic depth, can serve to avoid wastage of expensive anesthetics and expedite postanesthesia care unit or hospital discharge, or both. There have been several thoughtful discussions of the monitoring of depth of anesthesia and of the problem of awareness. Table 1 lists many of the techniques or devices that have been proposed or tested as methods for determining depth of anesthesia. A thorough discussion by Heier and Steen published in 1996 reviews the status of all but the most recent of those techniques. Briefly, the review leads to the conclusion that, although several techniques allow one to identify statistically significant differences in depth of anesthesia among defined anesthetic conditions for populations of patients, none has the sensitivity and specificity to allow the clinician to draw certain conclusions about depth of anesthesia in the individual patients for whom he or she treats. The then-available (1996) devices served as trend monitors of varying reliability but did not permit conclusive statements about depth of anesthesia in individual patients. The purpose of this review is to summarize the developments that postdate the articles cited previously. That progress has involved principally two depth-ofanesthesia monitoring methods: the Bispectral Index, known by the trademarked acronym BIS (Aspect Medical Systems Inc., Newton, MA); and the middle latency auditory evoked response (MLAER). The BIS is an empirically derived index that is dependent on a measure of the “coherence” among components of electroencephalography. The MLAER uses measurements of the amplitude and latency of the early cortical components of the auditory evoked response. This discussion will focus on developments related to those two methods. In addition, because of the interest on the part of the media, patients, practitioners, and investigators regarding the topic of awareness during anesthesia, the issue to which this review gives greatest attention is: Can the available monitors be used to prevent the occurrence of awareness during anesthesia? Professor and Chair, Department of Anesthesiology, University of California; Staff Anesthesiologist, Anesthesia Service, VA Medical Center, San Diego, California.

A Comparison of the Cerebrovascular and Metabolic Effects of Halothane and Isolflurane in the Cat

Halothane is a well known cerebral vasodilator that can produce dangerous increases in intracranial pressure (ICP) in certain neurosurgical patients. It has been suggested that isoflurane may be a less potent cerebral vasodilator. The authors therefore undertook a direct comparison of the effects of halothane and isoflurane on cerebral blood flow (CBF), cerebral vascular resistance (CVR), intracranial pressure, and cerebral metabolic rate for oxygen (CMRO2). Studies were carried out in normocarbic mechanically ventilated cats, using the intracarotid 133Xe injection technique to measure CBF. The effects of three doses were examined: 0.5, 1.0, and 1.5 MAC, studied in the continued presence of 75% N2O. Autoregulation also was tested at 1.0 MAC (plus 75% N2O) by recording CBF and CVR before and after elevation of blood pressure with angiotensin.Both agentes had similar effects on blood pressure and ICP. However, while halothane produced significant increases in CBF at all doses, with values of 61 ± 5 ml · 100 g-1 · min-1 (123 ± 8% of control, mean ± SE) at 1.0 MAC, isoflurane anesthesia caused no significant changes in CBF at any level, (e.g., 48 ± 8 ml · 100 g-1 · min-1 or 94 ± 12% of control at 1.0 MAC). Both drugs produced dose-related decreases in CVR, but the changes were greater with halothane, e.g., CVR at 1.0 MAC halothane = 1.46 ± 0.20 mmHg · ml-1 · 100 g · min (47 ± 7% of control) compared with 2.23 ± 0.40 mmHg · ml-1 · 100 g · min (72 ± 9% of control). In addition, isoflurane produced greater decreases in CMRO2 than did halothane, and also impaired autoregulation less.The results indicate that isoflurane possesses cerebrovascular properties that are different from halothane. These differences suggest that isoflurane may come to play an important role in future neuroanesthetic practice.

Inhibition of p75 Neurotrophin Receptor Attenuates Isoflurane-mediated Neuronal Apoptosis in the Neonatal Central Nervous System

Background:Exposure to anesthetics during synaptogenesis results in apoptosis and subsequent cognitive dysfunction in adulthood. Probrain-derived neurotrophic factor (proBDNF) is involved in synaptogenesis and can induce neuronal apoptosis via p75 neurotrophic receptors (p75NTR). proBDNF is cleaved into mature BDNF (mBDNF) by plasmin, a protease converted from plasminogen by tissue plasminogen activator (tPA) that is released with neuronal activity; mBDNF supports survival and stabilizes synapses through tropomyosin receptor kinase B. The authors hypothesized that anesthetics suppress tPA release from neurons, enhance p75NTR signaling, and reduce synapses, resulting in apoptosis. Methods:Primary neurons (DIV5) and postnatal day 5-7 (PND5-7) mice were exposed to isoflurane (1.4%, 4 h) in 5% CO2, 95% air. Apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Dendritic spine changes were evaluated with the neuronal spine marker, drebrin. Changes in synapses in PND5-7 mouse hippocampi were assessed by electron microscopy. Primary neurons were exposed to tPA, plasmin, or pharmacologic inhibitors of p75NTR (Fc-p75NTR or TAT-Pep5) 15 min before isoflurane. TAT-Pep5 was administered by intraperitoneal injection to PND5-7 mice 15 min before isoflurane. Results:Exposure of neurons in vitro (DIV5) to isoflurane decreased tPA in the culture medium, reduced drebrin expression (marker of dendritic filopodial spines), and enhanced Cl-Csp3. tPA, plasmin, or TAT-Pep5 stabilized dendritic filopodial spines and decreased Cl-Csp3 in neurons. TAT-Pep5 blocked isoflurane-mediated increase in Cl-Csp3 and reduced synapses in PND5-7 mouse hippocampi. Conclusion:tPA, plasmin, or p75NTR inhibition blocked isoflurane-mediated reduction in dendritic filopodial spines and neuronal apoptosis in vitro. Isoflurane reduced synapses and enhanced Cl-Csp3 in the hippocampus of PND5-7 mice, the latter effect being mitigated by p75NTR inhibition in vivo. These data support the hypothesis that isoflurane neurotoxicity in the developing rodent brain is mediated by reduced synaptic tPA release and enhanced proBDNF/p75NTR-mediated apoptosis.

Isoflurane delays but does not prevent cerebral infarction in rats subjected to focal ischemia.

Background: Several investigations have shown that volatile anesthetics can reduce ischemic cerebral injury. In these studies, however, neurologic injury was evaluated only after a short recovery period. Recent data suggest that injury caused by ischemia is a dynamic process characterized by continual neuronal loss for a prolonged period. Whether isoflurane-mediated neuroprotection is sustained after a longer recovery period is not known. The current study was conducted to compare the effect of isoflurane on brain injury after short (2-day) and long (14-day) recovery periods in rats subjected to focal ischemia. Metbods: Fasted Wistar-Kyoto rats were anesthetized with isoflurane and randomly allocated to an awake (n = 36) or an isoflurane (n = 34) group. Animals in both groups were subjected to focal ischemia by filament occlusion of the middle cerebral artery. Pericranial temperature was servocontrolled at 37°C throughout the experiment. In the awake group, isoflurane was discontinued and the animals were allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained at 1.5 times the minimum alveolar concentration. After 70 min of focal ischemia, the filament was removed. Animals were killed 2 days (awake, n = 18; isoflurane, n = 17) and 14 days (awake, n = 18; isoflurane, n = 17) after ischemia. The volumes of cerebral infarction and selective neuronal necrosis in the animals were determined by image analysis of hematoxylin and eosin-stained coronal brain sections. Results: Cortical and subcortical volumes of infarction were significantly less in the isoflurane 2-day group (26 ± 23 mm 3 and 17 ± 6 mm 3 , respectively) than in the awake 2-day group (58 ± 35 mm 3 , P < 0.01; and 28 ± 12 mm 3 , P < 0.01, respectively). By contrast, cortical and subcortical volumes of infarction in the awake (41 ± 31 mm 3 and 28 ± 16 mm 3 , respectively) and isoflurane (41 ± 35 mm 3 and 19 ± 8 mm 3 , respectively) 14-day groups were not different (cortex, P = 0.99; subcortex, P = 0.08). The volume of cortical tissue in which selective neuronal necrosis was observed, however, was significantly less in the isoflurane 14-day group (5 ± 4 mm 3 ) than in the awake 14-day group (17 ± 9 mm 3 , P < 0.01). The total number of necrotic neurons in the region of selective neuronal necrosis was significantly smaller in the isoflurane 14-day group than in the awake 14-day group (P < 0.01). Conclusion: Compared with the awake state, isoflurane reduced the extent of infarction assessed 2 days after focal ischemia in rats. At 14 days, however, only selective neuronal necrosis, but not infarction, was reduced by isoflurane. These results suggest that isoflurane delays but does not prevent cerebral infarction caused by focal ischemia. Isoflurane may attenuate the delayed development of selective neuronal necrosis in periinfarct areas in this animal model.

EFFECTS OF PROPOFOL, ETOMIDATE, MIDAZOLAM AND FENTANYL ON MOTOR EVOKED RESPONSES TO TRANSCRANIAL ELECTRICAL OR MAGNETIC STIMULATION IN HUMANS

The effects of propofol, etomidate, midazolam, and fentanyl on motor evoked responses to transcranial stimulation (tc-MERs) were studied in five healthy human volunteers. Each subject, in four separate sessions, received intravenous bolus doses of propofol 2 mg.kg-1, etomidate 0.3 mg.kg-1, midazolam 0.05 mg.kg-1, and fentanyl 3 micrograms.kg-1. Electrical tc-MERs (tce-MERs) were elicited with anodal stimuli of 500-700 V. Magnetic tc-MERs (tcmag-MERs) were elicited using a Cadwell MES-10 magnetic stimulator at maximum output. Compound muscle action potentials were recorded from the tibialis anterior muscle. Duplicate tce-MERs and tcmag-MERs were recorded before and up to 30 min after drug injection. Reproducible baseline tce-MERs (amplitude 4.7 +/- 0.43 (SEM) mV, latency 29.4 +/- 0.35 ms) and tcmag-MERs (amplitude 3.7 +/- 0.43 mV, latency 31.1 +/- 0.39 ms) were obtained in all subjects. Pronounced depression of tce-MER amplitude to 2% of baseline values (P less than 0.01) was observed 2 min after injection of propofol. Thirty minutes after injection of propofol, amplitude depression to 44% of baseline (P less than 0.05) was still present, despite an apparent lack of sedation. Midazolam caused significant (P less than 0.01) amplitude depression, e.g., tcmag-MER to 16% of baseline values 5 min after injection. Significant depression persisted throughout the 30-min study period. Fentanyl did not cause any statistically significant amplitude changes in this small population. Etomidate caused significant but transient depression of tc-MER amplitude. However, there was considerable intersubject variability. Latency did not change significantly after any drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Halothane, Enflurane, Isoflurane, and Nitrous Oxide on Somatosensory Evoked Potentials in Humans

Median nerve somatosensory evoked potentiais (SSEPs) were recorded in 21 healthy subjects anesthetized with halothane, isoflurane, or enflurance (with and without nitrous oxide) for abdominal or pelvic surgery. Recordings were made prior to induction, then at 0.5 MAC increaments of each valatile agent with 60% N2O up to 1.5 MAC, and, finally, at 1.5 MAC without N2O. All three volatile anesthetics produced dose-related reductions in the amplitude and increases in the latency of he cortical component of hte SSEP. These changes were most pronounced with enflurance nad least with halothane. At 1.5 MAC of each volatile agent, cortical latency decrease and amplutede increased when nitrous oxide was discontinued. The results suggests that in neurologically intact patients, end-tidal concentrations of 1. MAC halothane and 0.5 MAC enflurance or isoflurance (each in 60% N2O) can be compatible with effective with effective SSEP monitoring. Volatile anesthetic concentrations consistent with satisfactory somatosensory-evoked potential recording may be grater if N2O is not employed.

The effects of sevoflurane on cerebral blood flow, cerebral metabolic rate for oxygen, intracranial pressure, and the electroencephalogram are similar to those of isoflurane in the rabbit

The effects of 0.5 and 1.0 MAC end-tidal concentrations of sevo-flurane on intracranial pressure, cerebral metabolic rate for oxygen, cerebral blood flow, and the electroencephalogram were compared to those of equi-MAC concentrations of isoflurane in rabbits anesthetized with morphine-nitrous oxide. At 1.0 MAC end-tidal level, both sevoflurane and isoflurane caused a significant reduction in cerebral metabolic rate for oxygen of about 50%. Neither anesthetic caused a significant change in global cerebral blood flow or cortical cerebral blood flow during either 0.5 or 1.0 MAC administration. However, both sevoflurane and isoflurane caused small but significant increases in intracranial pressure during 0.5 MAC and 1.0 MAC administration. The electroencephalogram of animals anesthetized with 1.0 MAC of either anesthetic demonstrated a burst suppression pattern with no evidence of spike or seizure activity. The data suggest that the effects of sevofluranc on cerebral blood flow, cerebral metabolic rate for oxygen, intracranial pressure, and the electroencephalogram are indistinguishable from those of equivalent concentrations of isoflurane in the rabbit.

Mac for Halothane, Enflurane, and Isoflurane in the New Zealand White Rabbit: And a Test for the Validity of Mac Determinations

MAC determinations for halothane, enflurane, and isoflurane were performed in New Zealand white rabbits (n = 8, approximate age 6 months). The MAC values (+/-SD) were as follows: halothane 1.39 +/- 0.23%, enflurane 2.86 +/- 0.18%, and isoflurane 2.05 +/- 0.18%. Comparison of these results with published MAC values for other species suggests that the ratio of the potencies for any pairing of these three agents is constant from species to species. This observation provides a means for assessing the validity of preexisting or newly determined MAC values.

A Comparison of the Cerebral Protective Effects of Isoflurane and Barbiturates during Temporary Focal Ischemia in Primates

Isoflurane has protective properties during experimental global brain ischemia or hypoxia. However, this has not been evaluated in the more common case of focal ischemia, e.g., as caused by middle cerebral artery occlusion (MCAO). The authors therefore compared the effects of isoflurane, thiopental, and N2O/fentanyl anesthesia on neurologic and neuropathologic outcome in baboons subjected to 6 h of transorbital left MCAO. Prior to MCAO, animals were assigned to one of three groups: Group 1 (n = 7) received isoflurane (in O2/air) in concentrations sufficient to maintain deep burst suppression on the EEG (2.0% ± 0.5% inspired, mean ± SD); group 2 (n = 6) received thiopental (O2/air) in doses adequate to maintain similar EEG suppression (3.6 ± 0.7 g total); and group 3 (n = 6) received 60% N2O/40% O2 and fentanyl (25 μg/kg load, 3 μg · kg−1 · h−1 infusion). Efforts were made to keep mean arterial pressure (MABP) between ≈80 and 100 mmHg, using nitroprusside/hydralazine or phenylephrine/metaraminol, with PaCO2 at ≈30 mmHg. The selected anesthetic was established 45 min before MCAO, was maintained until 1 h after clip removal, and in decreasing concentrations for 5 h. Neurologic status was scored for 7 days and formalin-fixed brains were later sectioned for determination of infarction volume. Six of seven group 1 (isoflurane) animals were hemiplegic, and 7/7 had verified infarctions. By contrast, 4 of 6 group 2 (thiopental) animals were normal, with 2/6 having infarctions. Outcome in group 3 (N2O/fentanyl) was intermediate between groups 1 and 2 (3/6 hemiplegic, 4/6 with infarctions). Differences in the infarction rates between groups 1 and 2 was significant (P < 0.05), while a similar comparison of neurologic outcome scores achieved a P value of 0.055. Infarctions in group 1 were more hemorrhagic in character than in group 3 (groups 1 and 2 could not be meaningfully compared). These results must be considered in light of differences in MABP during the occlusion period; MABP in group 1 was ≈80 mmHg in spite of vasopressor use, while that in group 2 was ≈100 mmHg (in spite of vasodilators). Nevertheless, they fail to demonstrate any protective value of isoflurane anesthesia, at least when compared with thiopental.

The effect of high dose sodium thiopental on brain stem auditory and median nerve somatosensory evoked responses in humans.

Median nerve somatosensory evoked potentials (MnSSEPs), brain stem auditory evoked responses (BAERs), and the cortical electroencephalogram (EEG) were recorded in six patients during a 62·min infusion of sodium thiopental (STP) at a rate of 1.25 mg·kg−1·min−1 (total dose, 77.5 mg/kg). The EEG became isoelectric after 22 ± 8 (SD) min of STP infusion. Dose-related changes in the latencies and amplitudes of various evoked response wave forms were observed. However, in no instance was any component of either the MnSSEP or the BAER rendered unobtainable by STP administration. For the MnSSEP, progressive increases in the central conduction time (5.33 ± 0.41 ms preinduction vs. 7.46 ± 1.2 ms at t = 60 min) and in the latency of the cortical primary specific complex were observed simultaneously with significant reductions in the amplitude of the latter (2.10 ± 0.85 μV preinduction vs. 0.85 ± 0.55 μV at t = 60 min). Changes in the latency and amplitude of the response recorded over the upper cervical spine (C2) were not statistically significant in this small population. For the BAER, progressive and significant increases in the latencies of Waves I, III, V (e.g., Wave V latency: 6.16 ± 0.24 vs. 6.87 ± 0.31 ms) and in the I-III, III-V, and the I-V interwave latencies were observed. The amplitudes of the BAER components were not significantly altered. The authors conclude that the administration of a dose of STP in excess of twice that required to produce EEG isoelectricity can be compatible with effective monitoring of MnSSEPs and BAERs. However, STP produces dose-related changes in both evoked response wave forms, which must be considered in the interpretation of responses elicited during STP anesthesia.