Changes in the plasma protein-binding rate of remifentanil during cardiopulmonary bypass.

AIMS: Cardiopulmonary bypass (CPB) reduces the plasma protein-binding rate of some anaesthetics and can enhance their pharmacological effects by increasing the unbound drug fraction. However, whether these changes occur with remifentanil remains to be explored. We investigated the changes in the protein-binding rate of remifentanil during CPB compared with propofol. METHODS: Thirteen patients (≥18 years old) who were scheduled to undergo cardiovascular surgery with CPB were included. Arterial blood samples were collected to measure the plasma concentrations of remifentanil and propofol before CPB (T1), 30 (T2) and 60 (T3) minutes after the start of CPB, and 30 min after CPB discontinuation (T4). The samples were immediately centrifuged to separate the plasma after blood collection. Equilibrium dialysis was used to separate the unbound fraction. The remifentanil and propofol concentrations were measured by liquid chromatography-mass spectrometry. The protein-binding rate was calculated based on the total and unbound fraction of each drug. RESULTS: The remifentanil protein-binding rates at each time point were 27.9% ± 11.2% (T1), 13.5% ± 4.4% (T2), 14.0% ± 3.3% (T3) and 24.5% ± 6.9% (T4). The propofol protein-binding rates were 97.5% ± 0.7% (n = 4; T1), 95.8% ± 1.4% (T2), 95.3% ± 1.3% (T3) and 95.8% ± 1.1% (T4). The protein binding rates of both drugs decreased during CPB and reversed after CPB. The change in the unbound fraction was 1.2-fold for remifentanil and 1.7-1.9-fold for propofol. CONCLUSIONS: Unlike propofol, remifentanil might not demonstrate significantly enhanced pharmacological effects during CPB.

Predicted effect-site concentrations of remimazolam for i-gel insertion: a prospective randomized controlled study.

This study is the first to report 50% and 95% effect-site concentrations (EC50 and EC95, respectively) of the new short-acting benzodiazepine, remimazolam, for the successful insertion of i-gels with co-administration of fentanyl. Thirty patients (38 ± 5 years old, male/female = 4/26) were randomly assigned into five groups to receive one of five different remimazolam doses (0.1, 0.15, 0.2, 0.25, and 0.3 mg/kg bolus followed by infusion of 1, 1.5, 2, 2.5, and 3 mg/kg/h, respectively, for 10 min), which were designed to maintain a constant effect-site concentration of remimazolam at the time of i-gel insertion. At 6 min after the start of remimazolam infusion, all patients received 2 µg/kg fentanyl. i-gel insertion was attempted at 10 min and the success or failure of insertion were assessed by the patient response. Probit analysis was used to estimate the EC50 and EC95 values of remimazolam with 95% confidence intervals (CIs). In the five remimazolam dose groups, two, two, four, five, and six of the six patients in each group had an i-gel successfully inserted. Two patients in the lowest remimazolam dose group were conscious at the time of i-gel insertion and were counted as failures. The EC50 and EC95 values of remimazolam were 0.88 (95% CI, 0.65-1.11) and 1.57 (95% CI, 1.09-2.05) µg/ml, respectively. An effect-site concentration of ≥ 1.57 µg/ml was needed to insert an i-gel using remimazolam anesthesia, even with 2 µg/kg fentanyl. Trial registration: The study was registered in Japan Registry of Clinical Trials on 19 April 2021, Code jRCTs041210009.

Effects of volatile anesthetics on circadian rhythm in mice: a comparative study of sevoflurane, desflurane, and isoflurane.

PURPOSE: Volatile anesthetics affect the circadian rhythm of mammals, although the effects of different types of anesthetics are unclear. Here, we anesthetized mice using several volatile anesthetics at two different times during the day. Our objective was to compare the effects of these anesthetics on circadian rhythm. METHODS: Male adult C57BL/6 J mice were divided into eight groups (n = 8 each) based on the anesthetic (sevoflurane, desflurane, isoflurane, or no anesthesia) and anesthesia time (Zeitgeber time [ZT] 6-12 or ZT18-24). Mice were anesthetized for 6 h using a 0.5 minimum alveolar concentration (MAC) dose under constant dark conditions. The difference between the start of the active phase before and after anesthesia was measured as a phase shift. Clock genes were measured by polymerase chain reaction in suprachiasmatic nucleus (SCN) samples removed from mouse brain after anesthesia (n = 8-9 each). RESULTS: Phase shift after anesthesia at ZT6-12 using sevoflurane (- 0.49 h) was smaller compared with desflurane (- 1.1 h) and isoflurane (- 1.4 h) (p < 0.05). Clock mRNA (ZT6-12, p < 0.05) and Per2 mRNA (ZT18-24, p < 0.05) expression were different between the groups after anesthesia. CONCLUSION: 0.5 MAC sevoflurane anesthesia administered during the late inactive to early active phase has less impact on the phase shift of circadian rhythm than desflurane and isoflurane. This may be due to differences in the effects of volatile anesthetics on the expression of clock genes in the SCN, the master clock of the circadian rhythm.

Stomach, liver, kidney and skeletal muscle autoregulation evaluated by near-infrared spectroscopy in a swine model.

PURPOSE: Different organs have different autoregulatory capacities for blood pressure changes and/or circulatory volume changes. This study assessed the autoregulation of the stomach, liver, kidney and skeletal muscle, under baseline, hypovolemic, and post-fluid-resuscitation conditions using near-infrared spectroscopy (NIRS). METHODS: Ten pigs (bodyweight 24.5 ± 0.5 kg) were anesthetized with 2.5% isoflurane and administered 0.5, 1, 2 and 5 µg kg- 1 min- 1 of phenylephrine at 10-min intervals, followed by similar stepwise infusion of sodium nitroprusside (SNP) to induce a wide range of mean arterial pressures (MAPs). A 600-ml bleed was induced to create the hypovolemic condition, and only phenylephrine was re-administered. Hydroxyethyl starch (600 ml) was infused to create the post-fluid-resuscitation condition, and phenylephrine and SNP were re-administered. Average relationships between mean arterial pressure (MAP) and each tissue oxygenation index (TOI) were assessed, and the individual relationships were evaluated based on the correlation coefficients between MAP and TOI during each vasoactive drug infusion. RESULTS: Based on the evaluation using each TOI as a substitute of blood flow, the kidney autoregulation was robust, similar to muscle, but had a prominent lower limit. The stomach had weaker autoregulation than the kidney and muscle. The liver had no autoregulation. The kidney TOI showed 2-fold greater changes in response to volume condition changes than the stomach and liver TOIs. CONCLUSION: In our NIRS-based assessment of autoregulatory capacity, the liver oxygenation is highly blood pressure dependent, and the kidney is highly susceptible and the skeletal muscle is highly tolerable to low blood pressure and volume loss.

Association between remimazolam and postoperative delirium in older adults undergoing elective cardiovascular surgery: a prospective cohort study.

PURPOSE: Postoperative delirium is one of the most common complications after cardiovascular surgery in older adults. Benzodiazepines are a reported risk factor for delirium; however, there are no studies investigating remimazolam, a novel anesthetic agent. Therefore, we prospectively investigated the effect of remimazolam on postoperative delirium. METHODS: We included elective cardiovascular surgery patients aged ≥ 65 years at Hamamatsu University Hospital between August 2020 and February 2022. Patients who received general anesthesia with remimazolam were compared with those who received other anesthetics (control group). The primary outcome was delirium within 5 days after surgery. Secondary outcomes were delirium during intensive care unit stay and hospitalization, total duration of delirium, subsyndromal delirium, and differences in the Mini-Mental State Examination scores from preoperative to postoperative days 2 and 5. To adjust for differences in the groups' baseline covariates, we used stabilized inverse probability weighting as the primary analysis and propensity score matching as the sensitivity analysis. RESULTS: We enrolled 200 patients; 78 in the remimazolam group and 122 in the control group. After stabilized inverse probability weighting, 30.3% of the remimazolam group patients and 26.6% of the control group patients developed delirium within 5 days (risk difference, 3.8%; 95% confidence interval -11.5% to 19.1%; p = 0.63). The secondary outcomes did not differ significantly between the groups, and the sensitivity analysis results were similar to those for the primary analysis. CONCLUSION: Remimazolam was not significantly associated with postoperative delirium when compared with other anesthetic agents.

Influence of hemorrhage and subsequent fluid resuscitation on transcranial motor-evoked potentials under desflurane anesthesia in a swine model.

PURPOSE: Hemorrhage increases the effect of propofol and could contribute to false-positive transcranial motor-evoked potential (TcMEP) responses under total intravenous anesthesia (TIVA). We investigated the influence of hemorrhage and subsequent fluid resuscitation on TcMEPs under desflurane anesthesia. METHODS: Sixteen swine (25.4 ± 0.4 kg) were anesthetized with a 4% end-tidal desflurane concentration (EtDes), which was incrementally increased to 6%, 8%, and 10% and then returned to 4% every 15 min. This procedure was repeated twice (baseline). After baseline measurements, animals were allocated to either the hemorrhage (n = 12) or control (n = 4) group. In the hemorrhage group, 600 ml of blood was removed and the EtDes protocol described above was applied. Hypovolemia was resuscitated using 600 ml of hydroxyethyl starch and the EtDes protocol was applied again. TcMEPs were measured at each EtDes. In the control group, measurements were performed without hemorrhage or fluid infusion. RESULTS: TcMEP responses were observed in all conditions in all limbs with 4% EtDes (0.4 MAC). TcMEP amplitudes decreased according to the EtDes to a greater degree in the lower limbs compared with the upper limbs. Hemorrhage enhanced the effect of desflurane on TcMEP amplitudes, and decreased TcMEP by 41 ± 12% in upper limbs and 63 ± 17% in lower limbs compared with baseline. Subsequent fluid resuscitation did not reverse TcMEP amplitudes. CONCLUSIONS: TcMEP amplitudes decrease during hemorrhage under desflurane anesthesia. This phenomenon might result from an enhanced effect of desflurane on the spinal motor pathway without increasing the desflurane concentration.

Recall of extubation after remimazolam anesthesia with flumazenil antagonism during emergence: a retrospective clinical study.

PURPOSE: This study was performed to examine and compare the incidence of extubation recall in surgical patients who underwent remimazolam anesthesia with flumazenil antagonism during emergence and in those who underwent propofol anesthesia. METHODS: One hundred sixty-three patients who underwent surgery using general endotracheal or supraglottic airway anesthesia with propofol (n = 97) or remimazolam (n = 66) were retrospectively analyzed. Remimazolam was antagonized by flumazenil after discontinuation of remimazolam at the end of surgery. The endotracheal tube or supraglottic airway was removed after surgery was complete, and consciousness and adequate spontaneous breathing were confirmed. The incidence of extubation recall was compared between the remimazolam and propofol anesthesia groups using propensity score matching. RESULTS: Extubation recall was observed in 28 patients (17%). After propensity score matching, the incidence of extubation recall did not significantly differ between the remimazolam and propofol anesthesia groups (15.6% vs. 18.8%; p = 1.000). CONCLUSION: The incidence of extubation recall after remimazolam anesthesia with flumazenil antagonism during emergence did not significantly differ from that after propofol anesthesia.

Assessment of the benefits of head-up preoxygenation using near-infrared spectroscopy with pulse oximetry in a swine model.

Compared with supine positioning, head-up positioning improves preoxygenation and prolongs the time to oxygen desaturation. We reevaluated benefits of head-up positioning using near-infrared spectroscopy (NIRS) with pulse oximetry in a pig model. Six pigs (mean ± SD weight: 25.3 ± 0.6 kg) were anesthetized with isoflurane and evaluated in four positions-supine, head-up, head-down, head-up to supine-just before apnea (positions' order after "supine" was randomized). In each position, after 5 min of preoxygenation with 100% oxygen, apnea was induced and the time to SpO2 < 70% measured. Hemodynamic and blood-gas variables and the cerebral tissue oxygenation index (TOI) were evaluated using NIRS and recorded. Hypovolemia was induced by collecting 600 mL blood. Apnea experiment was performed again in each position. The times (seconds) ± SD to SpO2 < 70% were 108 ± 13 (supine), 138 ± 15 (head-up; P < 0.0001 vs all other positions); 101 ± 12 (head-down) and 106 ± 15 (head-up to supine) during normovolemia, and 110 ± 29, 120 ± 7 (not significant vs all other positions), 101 ± 16, and 106 ± 11, respectively, during hypovolemia. Although the TOI was not associated with the positions during normovolemia, the head-up position during hypovolemia decreased TOI from 62% ± 6% (supine) to 50% ± 9% (head-up; P = 0.0019) before preoxygenation, and it remained low during apnea. The head-up position improves preoxygenation, but repositioning to supine negates the benefits. Head-up positioning during evident hypovolemia should be avoided because the cerebral oxygenation could decrease.

1.2% Hydrogen gas inhalation protects the endothelial glycocalyx during hemorrhagic shock: a prospective laboratory study in rats.

PURPOSE: Hydrogen gas (H2) inhalation improved the survival rate of hemorrhagic shock. However, its mechanisms are unknown. We hypothesized that H2 protected the endothelial glycocalyx during hemorrhagic shock and prolonged survival time. METHODS: 83 Sprague-Dawley rats were anesthetized with isoflurane. The animals were randomly assigned to 5 groups: room air with no shock, 1.2% H2 with no shock, room air with shock (Control-S), 1.2% H2 with shock (H21.2%-S), and 3.0% H2 with shock (H23.0%-S). Shock groups were bled to a mean arterial pressure of 30-35 mmHg and held for 60 min, then resuscitated with normal saline at fourfold the amount of the shed blood volume. RESULTS: The syndecan-1 level was significantly lower in the H21.2%-S [8.3 ± 6.6 ng/ml; P = 0.01; 95% confidence interval (CI), 3.2-35.8] than in the Control-S (27.9 ± 17.0 ng/ml). The endothelial glycocalyx was significantly thicker in the H21.2%-S (0.15 ± 0.02 µm; P = 0.007; 95% CI, 0.02-0.2) than in the Control-S (0.06 ± 0.02 µm). The survival time was longer in the H21.2%-S (327 ± 67 min, P = 0.0160) than in the Control-S (246 ± 69 min). The hemoglobin level was significantly lower in the H21.2%-S (9.4 ± 0.5 g/dl; P = 0.0034; 95% CI, 0.6-2.9) than in the Control-S (11.1 ± 0.8 g/dl). However, the H23.0%-S was not significant. CONCLUSIONS: Inhalation of 1.2% H2 gas protected the endothelial glycocalyx and prolonged survival time during hemorrhagic shock. Therapeutic efficacy might vary depending on the concentration.

Effective Dose of Landiolol, an Ultra-Short-Acting ß-Blocker, to Decrease Heart Rate During On-Pump, Beating Coronary Artery Bypass Grafting.

OBJECTIVE: Decreasing the heart rate (HR) using landiolol, an ultra-short-acting ß-blocker, is helpful for completing a meticulous distal anastomosis during on-pump or off-pump, beating coronary artery bypass grafting (CABG) surgery. We determine the effectiveness of landiolol to decrease the HR because the most effective dose has not been established. DESIGN: Observational open-label pharmacodynamics cohort study. SETTING: Single center, Hamamatsu University Hospital. PARTICIPANTS: 28 patients undergoing on-pump, beating CABG. INTERVENTIONS: Landiolol 5 µg/kg/min was started (time 0) and then increased to 15, 25, and 35 µg/kg/min at 10-min intervals during left internal thoracic artery (LITA) to left anterior descending artery (LAD) anastomosis. MEASUREMENTS AND MAIN RESULTS: Pharmacodynamics were characterized using a sigmoidal inhibitory maximum effect model to determine the percent decrease in HR according to the landiolol dose. Baseline (mean  ±â€¯ SD) HR (85 ±â€¯10 beats/min) decreased to 81 ±â€¯9, 71 ±â€¯10, 67 ±â€¯9, and 67 ±â€¯9 beats/min, respectively, at the four landiolol infusion points evaluated. Estimated maximum percent decrease in HR from the baseline effective dose value (ED0) was -21.5 (-25.3 to -17.8) [mean (95% confidence interval)]%. ED50, ED90, and ED95 were 9.5 (9.0-10.1), 25.0 (22.5-27.6), and 35.2 (30.3-40.1) µg/kg/min, respectively. CONCLUSIONS: Landiolol maximally decreased HR just over 20% of the baseline HR. Hence, landiolol 25 µg/kg/min is likely a sufficient dose during LITA-LAD anastomosis during on-pump, beating CABG.

Assessment of cerebral and renal autoregulation using near-infrared spectroscopy under normal, hypovolaemic and postfluid resuscitation conditions in a swine model: An observational study.

BACKGROUND: The impact of blood pressure changes on tissue oxygenation differs between vital organs and with blood volume conditions. OBJECTIVE: To assess cerebral and renal autoregulation simultaneously and compare the impact of blood pressure, hypovolaemia and fluid resuscitation on tissue oxygenation using near-infrared spectroscopy. DESIGN: Animal observational study. SETTING: An animal laboratory in Hamamatsu University School of Medicine, Hamamatsu, Japan, from April 2018 to August 2018. ANIMALS: Fifteen pigs, (mean ±â€ŠSD) 25.2 ±â€Š0.4 kg. INTERVENTIONS: The pigs were anaesthetised with 2.5% isoflurane and phenylephrine 0.5, 1, 2 and 5 µg kg min was administered in a stepwise fashion at 10-min intervals (baseline), followed by similar administration of sodium nitroprusside. Hypovolaemia was induced by a 600-ml bleed (33% of estimated total blood volume). Then phenylephrine was administered again (same protocol). Hypovolaemia was reversed by infusion of 600-ml hydroxyethyl starch. Phenylephrine and sodium nitroprusside were then administered again (same protocol). MAIN OUTCOME MEASURES: Average of the relation between mean arterial pressure (MAP) and cerebral or renal tissue oxygenation index (TOI) and individual TOI response during vasoactive drug infusions. RESULTS: The average relationship between MAP and cerebral or renal TOI both showed classic autoregulation patterns, whereas the renal TOI was more pressure-dependent than the cerebral TOI. Hypovolaemia shifted the relationship downward, reducing the cerebral and renal TOIs by approximately 5 and 20%, respectively, at similar MAPs. Subsequent fluid resuscitation preserved the autoregulatory pattern in both organs, not changing cerebral TOI but reducing renal TOI to 10% under baseline. TOI responses in both organs included paradoxical changes (tissue oxygenation changed inversely with MAP) in 60% of animals. Animals with paradoxical reactions maintained more stable cerebral and renal oxygenation. CONCLUSION: Renal oxygenation is more pressure-dependent than pressure-tolerant cerebral oxygenation, and autoregulation is not robust. Renal oxygenation decreased four-fold compared with cerebral oxygenation during hypovolaemia and two-fold during isovolaemic anaemia. Thus, paradoxical responses are part of normal autoregulatory function and beneficial for maintaining stable oxygenation.

Dobutamine, a ß1 Adrenoceptor Agonist, Increases Cerebral Oxygenation During Acute Anemia and Apneic Hypoxia.

BACKGROUND: ß1 blockers increase the risk of cerebral hypoxia during acute anemia and apneic hypoxia. We hypothesized that ß1 stimulants conversely increase cerebral tolerance to anemia and hypoxia. METHODS: After induction with isoflurane, twelve swine (mean ± SD: 25.2 ± 0.6 kg) received 200 µg kg-1 min-1 landiolol and 20 µg kg-1 min-1 dobutamine. Reversal of the order of drug administration was performed in six animals each. Before and during each drug infusion, apnea was induced until reaching <70% oxygen saturation (SpO2) after 5 min of 100% oxygen ventilation. Hemodynamic and blood gas variables were measured, and the cerebral and peripheral tissue oxygenation index (TOI) was recorded by near-infrared spectroscopy (apnea experiment). Following this, anemia (isovolemic hemodilution) was induced and apnea experiments were conducted in three stages, similarly to those before anemia. RESULTS: Dobutamine increased cerebral TOI before apnea (fraction of inspired oxygen [FiO2]: 1.0), at 1 min after apnea, and at SpO2 < 70% by 7.9, 8.8, and 3.9%. Landiolol decreased TOI by 0.8, 2.6, and 4.4% from the respective values at baseline. During anemia, these changes decreased with dobutamine and increased with landiolol administration. Dobutamine (or landiolol) shifted the relationship between TOI and arterial hemoglobin oxygen saturation or arterial partial pressure of oxygen to the right (or left) and increased (or decreased) TOI at similar arterial blood oxygenation. CONCLUSIONS: Dobutamine increases cerebral oxygenation during hypoxia and/or anemia and might be effective in improving neurological outcomes in ischemic cerebral injury.

Randomized double-blind comparison of the effects of intramyometrial and intravenous oxytocin during elective cesarean section.

AIM: Obstetricians sometimes administer intramyometrial oxytocin to stimulate uterine contraction during cesarean section, but its effects have not been well investigated. We performed a randomized, double-blind study to test the hypothesis that a small dose of intramyometrial oxytocin would induce acceptable uterine contractility more quickly and with fewer hemodynamic side-effects than the same dose administered intravenously. METHODS: Forty women with a single fetus at ≥36 weeks of gestational age scheduled for elective cesarean section under spinal anesthesia were randomized to the intravenous and intramyometrial groups to receive oxytocin at 0.07 IU/kg. The drug was administered immediately after umbilical cord clamping. Systolic blood pressure, heart rate, intraoperative blood loss, uterine tone, total amount of intraoperative oxytocin, and additional uterotonic drugs administered in the first 24 h were compared. RESULTS: Maximum uterine contractility was achieved after 2 and 10 min for the intravenous and intramyometrial groups, respectively. The mean hemodynamic parameters of the intramyometrial group were stable. In contrast, the intravenous group showed a reduction in systolic blood pressure after 2-4 min and increased heart rate after 1-2 min. Intraoperative blood loss, total oxytocin dose, and frequency of additional uterotonic drugs were comparable between the two groups. CONCLUSION: Although intraoperative blood loss was comparable, a small dose of intramyometrial oxytocin was inappropriate to obtain a prompt and acceptable uterine contraction during cesarean section.

The Influence of Hypovolemia and Fluid Resuscitation During Hemorrhagic Shock on Apneic Oxygen Desaturation After Preoxygenation in a Swine Model.

BACKGROUND: Patients experiencing major bleeding often require both aggressive fluid resuscitation and rapid sequence tracheal intubation. The influence of hemorrhage-induced hypovolemia, and/or subsequent fluid resuscitation, on the time until critical oxygen desaturation is not well described. We studied the time to oxygen desaturation in a pig model of hemorrhage shock and colloid resuscitation. METHODS: After anesthetic induction with isoflurane, 9 swine (mean ± SD = 25.3 ± 0.6 kg) were studied with the use of a stepwise hemorrhage and fluid resuscitation model with 4 sequential stages: 600 mL hemorrhage, 600 mL hydroxyethyl starch infusion, a further 600 mL hemorrhage, and a second 600 mL hydroxyethyl starch infusion. At each stage, after 5 minutes of mechanical ventilation with 100% oxygen, we induced apnea and measured the time to oxygen desaturation (oxygen saturation [SpO2] <70%). Hemodynamic and blood gas variables were recorded, and the cerebral and peripheral tissue oxygenation indices were recorded by near-infrared spectroscopy. RESULTS: The times ± SD to SpO2 <70% at each stage were 136 ± 41 (baseline), 147 ± 41 (hemorrhage), 131 ± 38 (resuscitation), 147 ± 38 (repeat hemorrhage), and 134 ± 36 seconds (repeat resuscitation). The mean differences in times before and after hemorrhage were 11.2 (6.5 to 16.0, P = 0.0052) and 16.0 (11.0 to 21.0, P < 0.0001), respectively. PaO2 before and after apneic desaturation (at SpO2 < 70%) was not different between stages. On the basis of tissue oxygenation index findings, hypovolemia decreased oxygen consumption, and fluid resuscitation recovered this parameter. CONCLUSIONS: In patients with acute hemorrhagic shock, a hypovolemic state increases the duration of apnea until critical oxygen desaturation. Clinicians should thus consider the relationship between fluid resuscitation and time to desaturation when performing tracheal intubation in such patients.

Evaluation of near infrared spectroscopy for detecting the ß blocker-induced decrease in cerebral oxygenation during hemodilution in a swine model.

ß blockers reduce cerebral oxygenation after acute hemodilution and may contribute to the incidence of stroke when used perioperatively. The goal of the study was to investigate whether cerebral tissue oxygenation using near infrared spectroscopy can detect the ß blocker-induced decrease in cerebral oxygenation depending on the severity of hemodilution and/or the dose of ß blockers. Animals were anesthetized with 2% isoflurane and randomly assigned to a landiolol or esmolol group. After baseline measurement, landiolol or esmolol was administered at 40 µg/kg/min for 20 min, increased to 200 µg/kg/min for 20 min, and then stopped. Hemodynamic and arterial variables and the tissue oxygenation index (TOI) were recorded at each ß blocker dose. Two stages of hemodilution were sequentially induced by repeated hemorrhage of 600 ml (33% of estimated blood volume) and infusion of the same volume of hydroxyethylstarch. During each stage, landiolol or esmolol was similarly administered and measurements were made. Landiolol and esmolol both dose-dependently decreased heart rate, mean arterial pressure and cardiac output, depending on the severity of hemodilution. Landiolol at 40 µg/kg/min was almost equivalent in potency to 200 µg/kg/min esmolol for decreasing HR before hemodilution. Based on the TOI, short-acting ß blockers reduced cerebral oxygenation in a dose-dependent manner during hemodilution, and oxygenation returned to the baseline level after drug infusion was stopped. TOI may be useful for identification of a decrease in cerebral oxygenation for patients receiving ß blockade during surgery associated with major bleeding.

IMPACT OF HIGH-DOSE VASOPRESSOR DURING ENDOTOXIC SHOCK ON THE CEREBRAL, LINGUAL, HEPATIC, AND RENAL MICROCIRCULATION EVALUATED BY NEAR-INFRARED SPECTROSCOPY IN SWINE.

ABSTRACT: Background: High-dose vasopressors maintain blood pressure during septic shock but may adversely reduce microcirculation in vital organs. We assessed the effect of high-dose norepinephrine and vasopressin on the microcirculation of the brain, tongue, liver, and kidney during endotoxic shock using near-infrared spectroscopy (NIRS). Methods: Thirteen pigs (24.5 ± 1.8 kg) were anesthetized, and an NIRS probe was attached directly to each organ. Approximately 0.2, 0.5, 1, and 2 µg/kg/min of norepinephrine were administered in a stepwise manner, followed by 0.5, 1, 2, and 5 µg/kg/min of sodium nitroprusside in normal condition. Moreover, 1 µg/kg/h of lipopolysaccharide was administered continuously after 100 µg bolus to create endotoxic shock and after 1,000 mL of crystalloid infusion and high-dose norepinephrine (2, 5, 10, and 20 µg/kg/min) and vasopressin (0.6, 1.5, 3, and 6 U/min) were administered in a stepwise manner. The relationship between the MAP and each tissue oxygenation index (TOI) during vasopressor infusion was evaluated. Results: Three pigs died after receiving lipopolysaccharides, and 10 were analyzed. An increase of >20% from the baseline MAP induced by high-dose norepinephrine during endotoxic shock reduced the TOI in all organs except the liver. The elevation of MAP to baseline with vasopressin alone increased the kidney and liver TOIs and decreased the tongue TOI. Conclusion: Forced blood pressure elevation with high-dose norepinephrine during endotoxic shock decreased the microcirculation of vital organs, especially the kidney. Cerebral TOI may be useful for identifying the upper limit of blood pressure, at which norepinephrine impairs microcirculation.

[Pycnodysostosis: a case report].

A 53-year-old man suffered maxillar osteomyelitis and removal of sequester was scheduled under general anesthesia. Pycnodysostosis had been diagnosed in childhood and body height and weight were 148 cm and 40 kg, respectively. He presented facial dysmorphia, hypomobile mandible and narrow oral cavity. At the pre-anesthetic visit, we planned awake fiberscopic intubation before the induction of general anesthesia. On the day of surgery, however, face-mask ventilation was easily established with 100-microg dose of fentanyl. Thus, 70 mg of propofol was administered to achieve hypnosis and naso-tracheal intubation using fibrescope was accomplished. The patient's trachea was easily intubated without a decrease of pulse oximetry values and marked changes in cardiovascular parameters. Pycnodysostosis is a rare clinical entity; however, the airway difficulty was mild in the present case.

The influence of endotoxemia on the electroencephalographic and antinociceptive effects of isoflurane in a swine model.

BACKGROUND: We have previously reported that hemorrhagic shock decreases the minimum alveolar anesthetic concentration (MAC) of isoflurane but minimally alters the electroencephalographic (EEG) effect. In this study, we investigated the influence of endotoxemia on the EEG effect and the MAC of isoflurane. METHODS: Eighteen swine (25.7 +/- 2.3 kg) were anesthetized by inhalation of isoflurane. The inhaled concentration was decreased to 0.5% and maintained for 20 min, before being returned to 2% and maintained for a further 20 min. End-tidal isoflurane concentrations and spectral edge frequencies were recorded. Analysis of the pharmacodynamics was performed using a sigmoidal inhibitory maximal effect model for spectral edge frequencies versus effect-site concentration. After measurement of the EEG effect, MAC was determined using the dewclaw clamp technique in which movement in response to clamping is recorded. After completion of control measurements, infusion of lipopolysaccharide (LPS, 1 microg x kg(-1) x h(-1)) was started after a 100-microg bolus administration. After 1 h, the inhaled concentration of isoflurane was varied as in the control period, and the MAC was assessed again (LPS1h). The same procedures were also performed after 3 h of LPS infusion (LPS3h). RESULTS: Endotoxemia decreased the effect-site concentration that produced 50% of the maximal effect from 1.31% +/- 0.22% to 1.13% +/- 0.14% (LPS1h) and 1.03% +/- 0.22% (LPS3h) and decreased the MAC from 2.05% +/- 0.20% to 1.51% +/- 0.30% (LPS1h) and 1.21% +/- 0.29% (LPS3h). CONCLUSIONS: Endotoxemia increases both the hypnotic and antinociceptive effects of isoflurane, in contrast to hemorrhagic shock, and the extent of these alterations increases with progression of endotoxemia.

Landiolol, an ultra short acting beta1-blocker, improves pulmonary edema after cardiopulmonary resuscitation with epinephrine in rats.

PURPOSE: Epinephrine is frequently administered as an essential drug for cardiopulmonary resuscitation (CPR) in clinical situations. Unfortunately, epinephrine elicits unfavorable effects, for example pulmonary edema, both during and after CPR. We hypothesized that administration of landiolol during CPR with epinephrine would reduce the degree of pulmonary edema and improve survival. Therefore using a rat CPR model, we investigated the effect of landiolol with epinephrine on pulmonary and cardiac injury following CPR. METHODS: Twelve male Sprague-Dawley rats were allocated to Group-E (Gr.-E: 0.02 mg/kg epinephrine) and thirteen animals to Group-EL (Gr.-EL: 0.02 mg/kg epinephrine with 0.5 mg/kg landiolol). After tracheotomy, cardiac arrest was induced by obstructing the endotracheal tube. We measured the lung wet-to-dry (W/D) weight ratio to evaluate the degree of pulmonary edema 2 h after CPR. The hematocrit (Hct) difference between before and after CPR (Hct-D) was calculated. We measured the plasma levels of troponin-I (T-I) to evaluate the degree of cardiac injury. RESULTS: The lung W/D weight ratio in Gr.-E (6.4 +/- 1.06, mean +/- SD) was significantly higher than that for Gr.-EL (4.9 +/- 0.80, p < 0.01). Hct-D was significantly higher in Gr.-E (10.2 +/- 3.1%) than in Gr.-EL (5.2 +/- 3.5%, p < 0.01). We observed no difference in survival or difference of T-I. (Gr.-E: 2.62 +/- 0.51 ng/ml, Gr.-EL: 3.43 +/- 2.72 ng/ml). CONCLUSION: Administration of landiolol during CPR with epinephrine prevented the development of pulmonary edema and the increase in Hct during and after CPR.