Chiharu Negishi

Bispectral EEG Index during Nitrous Oxide Administration

Background Nitrous oxide (N2 O) is a commonly used sedative for painful diagnostic procedures and dental work. The authors sought to characterize the effects of N2 O on quantitative electroencephalographic (EEG) variables including the bispectral index (BIS), a quantitative parameter developed to correlate with the level of sedation induced by a variety of agents. Methods Healthy young adult volunteers (n = 13) were given a randomized sequence of N2 O/O2 combinations via face mask. Five concentrations of N2 O (10, 20, 30, 40, and 50% atm) were administered for 15 min (20 min for the first step). EEG was recorded from bilateral frontal poles continuously. At the end of each exposure, level of sedation was assessed using primarily the Observer Assessment of Alertness/Sedation (OAA/S) scale. Results One subject withdrew from the study because of emesis at 50% N (2) O. N2 O (50%) increased theta, beta, 40 - 50 Hz, and 70 - 110 Hz band powers. BIS and spectral edge frequency during 50% N2 O/O2 did not differ significantly from baseline values. Abrupt decreases from higher to lower concentrations frequently evoked a profound, transient slowing of activity. No significant change in OAA/S was detected during the study. Conclusions Although the spectral content of the EEG changed during N (2) O administration, reflecting some pharmacologic effect, the subjects remained cooperative and responsive throughout, and therefore N2 O can only be considered a weak sedative at the tested concentrations. Despite changes in the lower and higher frequency ranges of EEG activity, the BIS did not change, which is consistent with its design objective as a specific measure of hypnosis.

Comparable Postoperative Pulmonary Atelectasis in Patients Given 30% or 80% Oxygen during and 2 Hours after Colon Resection

BACKGROUND High concentrations of inspired oxygen are associated with pulmonary atelectasis but also provide recognized advantages. Consequently, the appropriate inspired oxygen concentration for general surgical use remains controversial. The authors tested the hypothesis that atelectasis and pulmonary dysfunction on the first postoperative day are comparable in patients given 30% or 80% perioperative oxygen. METHODS Thirty patients aged 18-65 yr were anesthetized with isoflurane and randomly assigned to 30% or 80% oxygen during and for 2 h after colon resection. Chest radiographs and pulmonary function tests (forced vital capacity and forced expiratory volume) were obtained preoperatively and on the first postoperative day. Arterial blood gas measurements were obtained intraoperatively, after 2 h of recovery, and on the first postoperative day. Computed tomography scans of the chest were also obtained on the first postoperative day. RESULTS Postoperative pulmonary mechanical function was significantly reduced compared with preoperative values, but there was no difference between the groups at either time. Arterial gas partial pressures and the alveolar-arterial oxygen difference were also comparable in the two groups. All preoperative chest radiographs were normal. Postoperative radiographs showed atelectasis in 36% of the patients in the 30%-oxygen group and in 44% of those in the 80%-oxygen group. Relatively small amounts of pulmonary atelectasis (expressed as a percentage of total lung volume) were observed on the computed tomography scans, and the percentages (mean +/- SD) did not differ significantly in the patients given 30% oxygen (2.5% +/- 3.2%) or 80% oxygen (3.0% +/- 1.8%). These data provided a 99% chance of detecting a 2% difference in atelectasis volume at an alpha level of 0.05. CONCLUSIONS Lung volumes, the incidence and severity of atelectasis, and alveolar gas exchange were comparable in patients given 30% and 80% perioperative oxygen. The authors conclude that administration of 80% oxygen in the perioperative period does not worsen lung function. Therefore, patients who may benefit from generous oxygen partial pressures should not be denied supplemental perioperative oxygen for fear of causing atelectasis.

Resistive-heating and forced-air warming are comparably effective

Serious adverse outcomes from perioperative hypothermia are well documented. Consequently, intraoperative warming has become routine. We thus evaluated the efficacy of a novel, nondisposable carbon-fiber resistive-heating system. Twenty-four patients undergoing open abdominal surgery lasting approximately 4 h were randomly assigned to warming with 1) a full-length circulating water mattress set at 42°C, 2) a lower-body forced-air cover with the blower set on high, or 3) a three-extremity carbon-fiber resistive-heating blanket set to 42°C. Patients were anesthetized with a combination of continuous epidural and general anesthesia. All fluids were warmed to 37°C, and ambient temperature was kept near 22°C. Core (tympanic membrane) temperature changes among the groups were compared by using factorial analysis of variance and Scheffe[Combining Acute Accent] F tests; results are presented as means ± SD. Potential confounding factors did not differ significantly among the groups. In the first 2 h of surgery, core temperature decreased by 1.9°C ± 0.5°C in the circulating-water group, 1.0°C ± 0.6°C in the forced-air group, and 0.8°C ± 0.2°C in the resistive-heating group. At the end of surgery, the decreases were 2.0°C ± 0.8°C in the circulating-water group, 0.6°C ± 1.0°C in the forced-air group, and 0.5°C ± 0.4°C in the resistive-heating group. Core temperature decreases were significantly greater in the circulating-water group at all times after 150 elapsed minutes; however, temperature changes in the forced-air and resistive-heating groups never differed significantly. Even during major abdominal surgery, resistive heating maintains core temperature as effectively as forced air. IMPLICATIONS: Efficacy was similar for forced-air and resistive heating, and both maintained intraoperative core temperature far better than circulating-water mattresses. We thus conclude that even during major abdominal surgery, resistive heating maintains core temperature as effectively as forced air.

The effects of physical treatment on induced fever in humans.

PURPOSE Initial treatments for fever include the amelioration of underlying causes and administration of antipyretic medications. However, patients who fail these treatments are often actively cooled, which may be counterproductive because decreasing skin temperature increases the thermoregulatory core target temperature. Cooling may also provoke metabolic and autonomic stress and thermal discomfort. SUBJECTS AND METHODS We studied 9 subjects, each on 3 days. Fever was induced each day with 100,000 IU/kg of interleukin-2 administered intravenously (elapsed time zero). Randomly assigned treatments were 1) control (a cotton blanket), 2) cooling (forced air at 15 degrees C), or 3) self-adjust (forced-air warming adjusted to comfort). Treatments were maintained for 3 to 8 elapsed hours. RESULTS Peak core temperatures (mean +/- SD) were 38.4 +/- 0.5 degrees C on the control day, 38.1 +/- 0.5 degrees C on the cooling day, and 38.5 +/- 0.4 degrees C on the self-adjust day. Integrated core temperatures were 6.0 +/- 1.6 degrees C x h on the control day, 5.7 +/- 2.2 degrees C x h on the cooling day, and 6.4 +/- 1.2 degrees C x h on the self-adjust day. Neither peak nor integrated core temperatures differed significantly on the 3 days. Shivering was common on the cooling day but otherwise rare. Oxygen consumption was normal on the control and self-adjust days but increased 35% to 40% during cooling (P = 0.0001). Mean arterial pressure and plasma norepinephrine and epinephrine concentrations were significantly greater during cooling (P <0.05). On a self-reported thermal comfort scale, the subjects were miserable during cooling and significantly more comfortable on the self-adjust than control day (P <0.05). CONCLUSION We conclude that active cooling should be avoided in unsedated patients with moderate fever, because it does not reduce core temperature but does increase metabolic rate, activate the autonomic nervous system, and provoke thermal discomfort.

The threshold for thermoregulatory vasoconstriction during nitrous oxide/sevoflurane anesthesia is reduced in the elderly

Elderly patients become more hypothermic during surgery, shiver less postoperatively, and take longer to rewarm than younger patients.Similarly, the vasoconstriction threshold (triggering core temperature) is reduced approximately 1 degrees C in elderly patients during nitrous oxide/isoflurane anesthesia. Accordingly, we tested the hypothesis that the vasoconstriction threshold in the elderly is also reduced approximately 1 degrees C during nitrous oxide and sevoflurane anesthesia. Eleven young patients aged 30-50 yr and 14 elderly patients aged 60-80 yr were anesthetized with nitrous oxide (50%) and sevoflurane (1%). Mean skin temperature was calculated from four sites. Fingertip blood flow was estimated using forearm minus fingertip skin-temperature gradients, with a gradient of 0 degrees C identifying onset of vasoconstriction. The distal esophageal temperature triggering onset of vasoconstriction identified the threshold for this thermoregulatory defense. The data from five patients who did not vasoconstrict at minimum core temperatures of 33-34 degrees C were eliminated, leaving 10 patients in each group. The vasoconstriction threshold was significantly less in the elderly (35.0 +/- 0.8 degrees C) than in younger patients (35.8 +/- 0.3 degrees C), despite similar mean skin temperatures (mean +/- SD, P < 0.01, Students t-test). Age dependence of thermoregulatory vasoconstriction during nitrous oxide/sevoflurane anesthesia is similar to that previously observed during nitrous oxide/isoflurane anesthesia. (Anesth Analg 1997;84:1029-33)

Opioids inhibit febrile responses in humans, whereas epidural analgesia does not: an explanation for hyperthermia during epidural analgesia.

BackgroundEpidural analgesia is frequently associated with hyperthermia during labor and in the postoperative period. The conventional assumption is that hyperthermia is caused by the technique, although no convincing mechanism has been proposed. However, pain in the “control” patients is inevitably treated with opioids, which themselves attenuate fever. Fever associated with infection or tissue injury may then be suppressed by opioids in the “control” patients while being expressed normally in patients given epidural analgesia. The authors therefore tested the hypothesis that fever in humans is manifested normally during epidural analgesia, but is suppressed by low-dose intravenous opioid. MethodsThe authors studied eight volunteers, each on four study days. Fever was induced each day by 150 IU/g intravenous interleukin 2. Volunteers were randomly assigned to: (1) a control day when no opioid or epidural analgesia was given; (2) epidural analgesia using ropivacaine alone; (3) epidural analgesia using ropivacaine in combination with 2 &mgr;g/ml fentanyl; or (4) intravenous fentanyl at a target plasma concentration of 2.5 ng/ml. ResultsFentanyl halved the febrile response to pyrogen, decreasing integrated core temperature from 7.0 ± 3.2°C · h on the control day, to 3.8 ± 3.0°C · h on the intravenous fentanyl day. In contrast, epidural ropivacaine and epidural ropivacaine–fentanyl did not inhibit fever. The fraction of core-temperature measurements that exceeded 38°C was halved by intravenous fentanyl, and the fraction exceeding 38.5°C was reduced more than fivefold. ConclusionsThese data support the authors’ proposed mechanism for hyperthermia during epidural analgesia. Fever during epidural analgesia should thus not be considered a complication of the anesthetic technique per se.

Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering.

Background Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined micro‐ and kappa‐agonist) treats shivering better than equianalgesic doses of pure micro‐opioid agonists. Meperidines special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure micro‐agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does. Methods Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 micro gram/ml; and (3) a target plasma alfentanil concentration of 0.2 micro gram/ml. Skin temperatures were maintained near 31 [degree sign] Celsius, and core temperatures were decreased by central‐venous infusion of cold lactated Ringers solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression. Results Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering. Conclusions The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidines special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

Isoflurane Alters Shivering Patterns and Reduces Maximum Shivering Intensity

Background Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core hypothermia), and maximum response intensity. Isoflurane produces a clonic muscular activity that is not a component of normal shivering. To the extent that clonic activity is superimposed on normal thermoregulatory shivering, the gain of shivering might be increased during isoflurane anesthesia. Conversely, volatile anesthetics decrease systemic oxygen consumption and peripherally inhibit skeletal muscle strength, which might limit maximum intensity despite central activation. The purpose of the present study was, therefore, to evaluate the effect of isoflurane shivering patterns and the gain and maximum intensity of shivering. Methods Ten volunteers were each studied in two separate protocols: (1) control (no drug) and (2) 0.7% end‐tidal isoflurane. On each day, the mean skin temperature was maintained at 31 [degree sign] Celsius. Core temperature was then reduced by infusion of cold fluid until shivering intensity no longer increased. The core temperature triggering the initial increase in oxygen consumption defined the shivering threshold. The gain of shivering was defined by the slope of the core temperature versus oxygen consumption regression. Pectoralis and quadriceps electromyography was used to evaluate anesthetic‐induced facilitation of clonic (5–7 Hz) muscular activity. Results Isoflurane significantly decreased the shivering threshold from 36.4 +/‐ 0.3 to 34.2 +/‐ 0.8 [degree sign] Celsius. The increase in oxygen consumption was linear on the control day and was followed by sustained high‐intensity activity. During isoflurane administration, shivering was characterized by bursts of intense shivering separated by quiescent periods. Isoflurane significantly increased the gain of shivering (as calculated from the initial increase), from ‐684 +/‐ 266 to ‐1483 +/‐ 752 ml [center dot] min sup ‐1 [center dot] [degree sign] Celsius sup ‐1. However, isoflurane significantly decreased the maximum intensity of shivering, from 706 +/‐ 144 to 489 +/‐ 80 ml/min. Relative electromyographic power in frequencies associated with clonus increased significantly when the volunteers were given isoflurane. Conclusions These data indicate that isoflurane anesthesia markedly changes the overall pattern of shivering during progressive hypothermia from a linear increase to an unusual saw‐tooth pattern. They further suggest that clonic muscular activity combines with shivering to increase the initial gain of shivering during isoflurane anesthesia, but that isoflurane peripherally inhibits the maximum expression of shivering.

Alfentanil reduces the febrile response to interleukin-2 in humans.

Objective: Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the μ‐receptor agonist alfentanil reduce fever magnitude. Design: Prospective, randomized, crossover study. Setting: Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco. Patients: Eight healthy male volunteers, aged 25‐31 yrs, each studied on three separate days. Intervention: Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)‐2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs. Methods and Main Results: Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5 ± 2.2°C·hr on the control day, to 4.9 ± 1.5°C·hr with 100 ng/mL alfentanil, and to 5.1 ± 1.7°C·hr with 200 ng/mL alfentanil (p = .011). Peak temperatures were also significantly reduced from 38.5 ± 0.4°C on the control day, to 38.0 ± 0.4°C on the 100 ng/mL‐alfentanil day and 38.0 ± 0.6°C on the 200‐ng/mL day (p = .019). Plasma cytokine concentrations increased after IL‐2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups. Conclusion: Alfentanil significantly reduced the febrile response to IL‐2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.

Desflurane reduces the febrile response to administration of interleukin-2

Background Intraoperative fever is relatively rare considering how often pyrogenic causes are likely to be present and how common fever is postoperatively. This low incidence suggests that general anesthesia per se inhibits the normal response to pyrogenic stimulation. The authors therefore tested the hypothesis that desflurane‐induced anesthesia produces a dose‐dependent inhibition of the febrile response. Methods Eight volunteers were studied, each on 3 study days. Each was given an intravenous injection of 50,000 IU/kg of interleukin‐2 (elapsed time, 0 h), followed 2 h later by 100,000 IU/kg. One hour after the second dose, the volunteers were assigned randomly to three doses of desflurane to induce anesthesia: (1) 0.0 minimum alveolar concentration (MAC; control), (2) 0.6 MAC, and (3) 1.0 MAC. Anesthesia continued for 5 h. Core temperatures were recorded from the tympanic membrane. Thermoregulatory vasoconstriction was evaluated using forearm‐minus‐fingertip skin temperature gradients; shivering was evaluated with electromyography. Integrated and peak temperatures during anesthesia were compared with repeated‐measures analysis of variance and Scheffes F tests. Results Values are presented as mean +/‐ SD. Desflurane reduced the integrated (area under the curve) febrile response to pyrogen, from 7.7 +/‐ 2.0 [degree sign]C [center dot] h on the control day to 2.1 +/‐ 2.3 [degree sign]C [center dot] h during 0.6 MAC and to ‐1.4 +/‐ 3.1 [degree sign]C [center dot] h during 1.0 MAC desflurane‐induced anesthesia. Peak core temperature (elapsed time, 5–8 h) decreased in a dose‐dependent fashion: 38.6 +/‐ 0.5 [degree sign]C on the control day, 37.7 +/‐ 0.7 [degree sign]C during 0.6 MAC and 37.2 +/‐ 1.0 [degree sign]C during 1.0 MAC desflurane anesthesia. Rising core temperature was always associated with fingertip vasoconstriction and often with shivering. Conclusions Desflurane‐induced anesthesia produced a dose‐dependent decrease in integrated and peak core temperatures after administration of pyrogen, with 1.0 MAC essentially obliterating fever. Anesthetic‐induced inhibition of the pyrogenic response is therefore one reason that fever is an inconsistent clinical response to inflammation during surgery.