Peter M. Winter

Regional brain activity changes associated with fentanyl analgesia elucidated by positron emission tomography

Recent positron emission tomography (PET) studies have demonstrated areas of pain processing in the human brain.Given the inhibitory effects of opioids on neuronal activity, we predicted that fentanyls analgesic effects would be associated with suppression of pain-evoked responses in these distinct brain areas. To test this, PET was used to measure cerebral blood flow responses, as reflections of regional neuronal activity, to painful and nonpainful thermal stimuli both in the absence and presence of fentanyl in humans. During each PET scan in nine healthy volunteers a tonic heat source was placed against the subjects left forearm, delivering a preset temperature of either 40 degrees C (nonpainful) or 47-48 degrees C (painful). Subjects underwent eight blood flow studies, each consisting of 50 mCi [(15) O]water injection and a PET scan. The first four studies were performed during placebo administration in the stimulus sequence: nonpainful, painful, painful, nonpainful. This sequence was then repeated during intravenous (IV) administration of fentanyl 1.5 mg/kg. Significant differences in regional cerebral blood flow (rCBF) between the placebo and the fentanyl conditions during nonpainful and painful stimuli were identified using statistical parametric mapping. It was found that pain increased rCBF in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, and contralateral supplementary motor area. Fentanyl increased rCBF in the anterior cingulate and contralateral motor cortices, and decreased rCBF in the thalamus (bilaterally) and posterior cingulate during both stimuli. During combined pain stimulation and fentanyl administration, fentanyl significantly augmented pain-related rCBF increases in the supplementary motor area and prefrontal cortex. This activation pattern was associated with decreased pain perception, as measured on a visual analog scale. In contrast to our hypothesis, these data indicate that fentanyl analgesia involves augmentation of painevoked cerebral responses in certain areas, as well as both activation and inhibition in other brain regions unresponsive to pain stimulation alone. (Anesth Analg 1997;84:120-6)

Human brain activity response to fentanyl imaged by positron emission tomography.

Positron emission tomography (PET) is a noninvasive imaging technique that can be used to observe drug actions on human brain in vivo.We used15 O-water PET scanning in six volunteers to examine the effects on regional cerebral activity as reflected by regional cerebral blood flow (rCBF) of a small intravenous bolus of fentanyl. rCBF was compared between scans obtained after fentanyl or a placebo using three separate statistical criteria including a pixel-by-pixel t statistic; significance was stringently defined at P values < 0.01. Anatomic locations of regional cerebral activity changes were verified by aligning rCBF PET scans with cranial magnetic resonance images using mathematical coregistration. Fentanyl administration was associated with significant increases in rCBF consistent with regional neuronal activation in both cingulate and orbitofrontal and medial prefrontal cortices, as well as caudate nuclei. These areas are responsive to nociceptive stimuli and are involved in avoidance learning, reward and addiction, visceromotor control, maintenance of attention, and pain-related affective behavior. Significant decreases were noted in both frontal and temporal areas and the cerebellum, a distribution far less extensive than that of opiate receptors in general. These data indicate that fentanyls effects are highly localized and specifically affect cerebral regions associated with a range of pain-related behaviors. (Anesth Analg 1996;82:1247-51)

Continuous Monitoring of Arterial Oxygen Saturation with Pulse Oximetry during Transfer to the Recovery Room

The incidence of hypoxemia in the immediate postoperative period was determined using a pulse oximeter for continuous monitoring of arterial oxygen saturation (Sao2) in 95 ASA class I or II adult patients breathing room air during their transfer from the operating room to the recovery room. Hypoxemia was defined as 90% Sao2 (arterial oxygen partial pressure (PaO2) ≅ 58 mm Hg). Severe hypoxemia was defined as 85% Sao2 (PaO2 ≅ 50 mm Hg). Hypoxemia occurred in 33 (35%) patients; severe hypoxemia occurred in 11 (12%). Postoperative hypoxemia did not correlate significantly with anesthetic agent, age, duration of anesthesia, or level of consciousness. There was a statistically significant correlation (P < 0.05) between hypoxemia and obesity. All three patients with a history of mild asthma became severely hypoxemic even though none had perioperative evidence of obstructive disease, also a statistically significant (P < 0.003) finding.

Cardiovascular Depression Secondary to Ionic Hypocalcemia during Hepatic Transplantation in Humans

Cardiovascular function, serum ionized calcium (Ca+2), and serum citrate were measured intraoperatively in patients (n = 9) undergoing orthotopic hepatic homotransplantation. Serum citrate increased 20-fold (P < 0.0006) following transfusion of citrated blood products in the absence of a functional liver. Serum ionized calcium decreased (P < 0.003) with concomitant decreases in cardiac index (P < 0.005), stroke index (P < 0.004), and left ventricular stroke work index (P < 0.001). Hemodynamic depression and ionic hypocalcemia were reversed following the administration of CaCl2. In contrast to patients with normal hepatic function, who may tolerate large amounts of citrated blood, patients with end-stage liver disease demonstrate acute ionic hypocalcemia with concomitant hemodynamic depression when receiving citrated blood products during the course of hepatic transplantation.

In vivo imaging of human limbic responses to nitrous oxide inhalation.

Human behavioral studies have shown that nitrous oxide, in subanesthetic concentrations, impairs psychomotor function, cognitive performance, and learning and memory processes.However, the cerebral mechanisms of such effects remain unknown. Positron emission tomography (PET) was used to map the brain areas associated with nitrous oxide effects. Regional cerebral blood flow (rCBF) was measured in eight volunteers, during room air (control) or 20% nitrous oxide (nitrous oxide) inhalation using15 O-water, to reflect regional neuronal activity. To control for the possibility that 20% nitrous oxide uncoupled cerebral blood flow and metabolism, in four of the subjects, regional cerebral metabolic rate (rCMR) was also measured using18 F-deoxyglucose during the two experimental conditions. Results of rCBF and rCMR scans were compared between conditions using the statistical parametric mapping method, and areas of nitrous oxide-related activation or deactivation were identified at a significance level of 0.005. Percent changes in rCBF scan pixels from these activated or deactivated areas were then compared with those of stereotactically corresponding rCMR scan pixels with t statistics (P < 0.05 was defined as a significant difference). It was found that cerebral blood flow and metabolism were not uncoupled by 20% nitrous oxide, since percent changes in rCBF and rCMR, detected during nitrous oxide inhalation, did not differ significantly from each other (P < 0.05). Nitrous oxide inhalation was associated with significant activation in the anterior cingulate cortex, a limbic area known to mediate psychomotor and cognitive processes. Deactivation was found in the posterior cingulate, hippocampus, parahippocampal gyrus, and visual association cortices in both hemispheres; the former two regions are known to mediate learning and memory. These areas identified by PET in vivo may provide the neuroanatomical basis for the behavioral responses associated with subanesthetic nitrous oxide inhalation. (Anesth Analg 1996;83:291-8)

Behavioral effects of trace and subanesthetic halothane and nitrous oxide in man.

: Using tests of complex reaction time and of immediate recall (digit span), the authors could not demonstrate that trace concentrations of halothane (to 0.02 per cent, or 200 parts per million) or halothane plus nitrous oxide (0.002 per cent plus 0.05 per cent, respectively) or nitrous oxide alone (0.4 per cent) affected mental function of male volunteers. However, subanesthetic concentrations of both nitrous oxide (20 to 30 per cent) and halothane (0.2 per cent) did impair mental function.

Naloxone Does Not Antagonize General Anesthesia in the Rat

The administration of naloxone 2, 10, 50, or 250 mg/kg intravenously did not alter halothane requirement (MAC) in Sprague-Dawley rats (12 rats per group). Two rats convulsed when given 50 mg/kg while anesthetized with halothane. In a separate group of awake rats, seven of nine animals convulsed when given naloxone, 100 mg/kg. It is concluded that any effect of naloxone on anesthetic requirement must be small (not significant in our study), and that if an effect exists it is the result of a nonspecific analeptic action of naloxone rather than a specific action at opiate receptors.

In vivo imaging of nitrous oxide-induced changes in cerebral activation during noxious heat stimuli.

Background Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Positron emission tomography was used in nine volunteers to identify the loci of nitrous oxide‐modulated cerebral responses to a peripheral noxious stimulus. Methods Nitrous oxide‐pain interactions were studied by comparing regional cerebral blood flow responses to a 48 degrees Celsius tonic heat stimulus, applied to each volunteers left forearm, during room air inhalation with those obtained while 20% nitrous oxide was administered. Two cerebral blood flow scans were obtained with the15 O‐water technique during each condition. Locations of specific regional activation related to pain, and nitrous oxide, were identified using the statistical parametric mapping method, with a significance level of P < 0.01. Pain was rated by visual analog scale and the values were compared using Wilcoxon rank sum analysis. Results Pain produced cerebral activation in the contralateral thalamus, anterior cingulate, and supplementary motor area. Adding nitrous oxide during pain stimulation abolished activation in these areas but was associated with activation in the contralateral infralimbic and orbitofrontal cortices. In parallel, mean visual analog scale scores decreased significantly from 67 +/‐ 4 (SEM) to 54 +/‐ 5 (P < 0.05). Conclusions Nitrous oxide, at 20% concentration, appears to modulate pain processing in the brains medial pain system, and also activates the infralimbic and orbitofrontal cortices. The potential contribution of the affected brain areas to nitrous oxide analgesia is discussed.

Assessment of Ventilation-Perfusion Inequalities by Arterial—Alveolar Nitrogen Differences in Intensive-care Patients

Gas-exchange units in the lung with low &OV0312;/&OV0422; give rise to an oxygen partial pressure lower in arterial blood than alveolar gas (A-aDi>.) an N2 partial pressure higher in arterial blood than in “ideal” mixed alveolar gas (a-ADx2). Both &OV0312;/&OV0422; maldistribution and direct right-to-left shunts can contribute to the A-aDo, but only low &OV0312;/&OV0422; will cause an a-ADx2. Twenty patients from an intensive care unit were studied by measurement of the A-aDo2. and a-ADx. In 14 patients breathing an enriched oxygen mixture A-aDo.’s averaged 183 mm Hg and a-ADx.’s, 69 mm Hg. In six patients breathing room air the mean A-aDo. was 47 mm Hg; three had no a-ADx.; the other three had a mean a-ADx. of 19 mm Hg. Hence, 17 of the 20 patients showed evidence of &OV0312;/&OV0422; mismatching. Using a two-compartment model, a mixing equation was derived to calculate the percentage flow (&OV0422;o/&OV0422;T) in a compartment with a &OV0312;/&OV0422; of essentially 0 necessary to produce the measured a-ADx,. This value ranged from 9 to 46 per cent of the cardiac output in those patients with a-ADx,’s. The classic technique of separating the &OV0312;/&OV0422; component of the A-aDo, by 100 per cent oxygen breathing was found to be misleading in eight of ten cases when compared with the a-ADx, method of assessing maldistribution. It appeared that units with low &OV0312;/&OV0422; became atelectatic when 100 per cent oxygen was breathed. It was postulated that the areas of low &OV0312;A/&OV0422; occur as a result of intermittent airway closure in the most dependent areas of the lung and also in the case of interstitial pulmonary edema with airway narrowing.

Naloxone Does Not Antagonize the Analgesic Effects of Inhalation Anesthetics

A previous demonstration that the ratio of analgesic to anesthetic end-points is not constant across inhalation anesthetic agents implies that more than one mechanism of action may be operant in general anesthesia. We hypothesized that the endogenous opiate systems might account for this observed disparity in ratios. The tail flick ED50 (TFED50) in response to a heat stimulus, as an index of analgesia, and MAC as an index of anesthesia, were determined in rats treated with either saline or naloxone, 20 mg/kg, and exposed to halothane, enflurane, or isoflurane. Our findings confirmed those of Deady et al., showing a lack of uniformity of ratios of TFED50/MAC, with values of 0.90 ± 0.03 for halothane, 0.80 ± 0.04 for enflurane, and 0.70 ± 0.04 for isoflurane. Naloxone had no effect on TFED50, MAC, or their ratio. If the endogenous opiate system were involved in the analgesic effect of general anesthetics, naloxone would have affected the ratios. We conclude that opiate systems are not involved in the analgesic action of general anesthetics.