Tomoki Nishiyama

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study

IntroductionFever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.MethodsWe designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.ResultsWe recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.Trial registrationClinicalTrials.gov: NCT00940654

Effects of Intrathecal NMDA and Non-NMDA Antagonists on Acute Thermal Nociception and Their Interaction with Morphine

Background N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a [micro sign]-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists would be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception. Methods Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine-ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle-and were tested for their effect on the response latency using a 52.5 [degree sign]C hot plate. The combinations of morphine and other agents also were tested. Results Intrathecal morphine (ED50:2 [micro sign]g/95% confidence interval, 1-4 [micro sign]g) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose- response curves were carried out for morphine and fixed doses of ACEA 1021 (12 [micro sign]g) or AP-5 (10 [micro sign]g). No synergistic interactions were noted. Conclusions Spinal [micro sign]-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.

Interaction between intrathecal morphine and glutamate receptor antagonists in formalin test

The analgesic interaction between intrathecally administered morphine and the NMDA receptor antagonist, ((+/-)-2-amino-5-phosphonopentanoic acid; AP-5), the NMDA receptor glycine site antagonist, (5-nitro-6,7-dichloro-2,3-quinoxaline dion; ACEA 1021), or the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonist (ACEA 2752) in the formalin test was investigated with a rat model of chronic lumbar intrathecal catheterization. After obtaining dose-response curves for each agent, combinations of morphine and AP-5, ACEA 1021 or ACEA 2752 were tested for their effect on the number of flinches in the formalin test and for associated side-effects, such as motor disturbances, flaccidity, and agitation/allodynia. Using isobolographic analyses, a potent analgesic synergy was observed with decreased side-effects between morphine and ACEA 2752 or AP-5. ACEA 1021 increased the analgesic effect of low-dose morphine. Spinal mu-opioid receptor activation and NMDA or AMPA receptor antagonism showed a synergistic antinociception against tonic pain. These results suggest an important direction in the management of inflammatory pain.

Cardiothoracic Anesthesia, Respiration and Airway Cardiac output by PulseCO™ is not interchangeable with thermodilution in patients undergoing OPCAB

PurposeTo investigate the reliability of cardiac output assessed by arterial pressure waveform (PulseCO™) in comparison with bolus thermodilution measurements in patients undergoing off-pump coronary artery bypass grafting (OPCAB).Methods23 patients who underwent OPCAB were enrolled in this study. After premedication with oral diazepam 10 mg, anesthesia was induced with midazolam, fentanyl and vecuronium. After induction, radial artery and pulmonary artery catheters were inserted. Cardiac output was measured simultaneously by the PulseCO™ and the bolus thermodilution method using the Vigilance™ monitor: 1) after sternotomy, 2) after opening the mediastinum, and 3) at the end of surgery. The PulseCO™ was calibrated initially with cardiac output determined by the thermodilution method after induction of anesthesia.ResultsThe correlation coefficients between the two techniques at the three measurement periods were: 1) R2 = 0.49, 2) R2 = 0.52, 3) R2 = 0.55. The limits of agreement (bias ± 2 SD of bias) were: 1) 0.71 ± 2.66, 2) 0.30 ± 1.97, 3) 0.76 ± 3.85 L·min-1. Conclusions: Cardiac output by PulseCO™ is not interchangeable with cardiac output measured by thermodilution in patients undergoing OPCAB.RésuméObjectifVérifier la fiabilité de l’évaluation du débit cardiaque par ondes de tension artérielle (PulseCO™) comparées à la thermodilution de bolus chez des patients devant subir un pontage aortocoronarien à coeur battant (PACCB).MéthodeL’étude a porté sur 23 patients devant subir un PACCB. Une prémédication orale de 10 mg de diazépam a été administrée, puis l’anesthésie a été induite avec du midazolam, du fentanyl et du vécuronium. Après l’induction, des cathéters ont été insérés dans les artères radiale et pulmonaire. Le débit cardiaque a été mesuré simultanément par PulseCO™ et par la méthode de thermodilution de bolus en utilisant le moniteur Vigilance™ : 1) après la sternotomie 2) après l’ouverture du médiastin et 3) à la fin de l’opération. Le PulseCO™ a été calibré au départ avec le débit cardiaque mesuré par la thermodilution après l’induction de l’anesthésie.RésultatsLes coefficients de corrélation entre les deux techniques et à trois périodes de mesures différentes ont été : 1) R2 = 0,49 2) R2 = 0,52 3) R2 = 0,55. Les limites de concordance (biais ± 2 écarts types de biais) ont été : 1) 0,71 ± 2,66, 2) 0,30 ± 1,97, 3) 0,76 ± 3,85 L·min-1.ConclusionLa mesure du débit cardiaque avec le PulseCO™ n’est pas interchangeable avec la mesure réalisée par thermodilution chez des patients devant subir un PACCB.Purpose: To investigate the reliability of cardiac output assessed byarterial pressure waveform (PulseCO™) in comparison with bolusthermodilution measurements in patients undergoing off-pumpcoronary artery bypass grafting (OPCAB).Methods: 23 patients who underwent OPCAB were enrolled inthis study. After premedication with oral diazepam 10 mg, anesthe-sia was induced with midazolam, fentanyl and vecuronium. Afterinduction, radial artery and pulmonary artery catheters were insert-ed. Cardiac output was measured simultaneously by thePulseCO™ and the bolus thermodilution method using theVigilance™ monitor: 1) after sternotomy, 2) after opening the medi-astinum, and 3) at the end of surgery. The PulseCO™ was calibrat-ed initially with cardiac output determined by the thermodilutionmethod after induction of anesthesia. Results: The correlation coefficients between the two techniquesat the three measurement periods were: 1) R

Propofol-induced bronchoconstriction: two case reports.

IMPLICATIONS Bronchoconstriction was induced by anesthetic induction with propofol in two patients with allergic diseases. One had severe bronchospasm improved by epinephrine. Propofol should be used with caution in patients with allergic disease.

Free hemoglobin concentrations in patients receiving massive blood transfusion during emergency surgery for trauma

Purpose: To determine free hemoglobin concentration in patients who received massive blood transfusion during emergency surgery for trauma with consideration of the storage of the transfused blood.Methods: Fifteen patients undergoing emergency surgery for multiple trauma and who received blood transfusion of more than 5,000 mL were studied. Transfusion of the stored whole blood in citrate-phosphate glucose solution using a micropore filter was started before surgery. Serum concentrations of hemoglobin (total: THb and free:fHb) and total haptoglobin (THp) were measured until 5,000 mL of blood had been transfused. Serum free haptoglobin (fHp) concentration was calculated. The correlation between the changes in hemoglobin or haptoglobin concentrations and total storage days of the transfused blood was analyzed by a simple regression analysis.Results: Free hemoglobin was detected after 2,000 mL transfusion. The THp and fHp decreased after 1,000 mL transfusion. Total storage time (days) of transfused blood had correlated with the changes of THp (P<0.0001) and fHp (P=0.0027) but not with the changes of THb (P=0.984) and fHb (P=0.834).Conclusion: After blood transfusion during surgery for trauma, serum haptoglobin concentration decreased with transfusion of ≥1,000 mL of whole blood with mean storage time of 12.2 dy. Free hemoglobin was detected after 2,000 mL transfusion when THp decreased to 1,000 mg·L−1. Serum haptoglobin concentrations correlated negatively with storage time (days) of transfused blood.RésuméObjectif: Déterminer la concentration d’hémoglobine libre chez des patients qui reçoivent une transfusion sanguine massive, pendant une opération urgente pour trauma, en considérant le temps de conservation du sang transfusé.Méthode: L’étude a porté sur 15 patients polytraumatisés, opérés d’urgence, qui ont reçu une transfusion de plus de 5 000 mL de sang. Avant l’intervention, on a commencé la transfusion de sang complet, conservé dans une solution de glucose citrate-phosphate, en utilisant un filtre micropore. Les concentrations sériques d’hémoglobine (totale: HbT et libre: Hbl) et d’haptoglobine totale (HpT) ont été mesurées jusqu’à ce que 5 000 mL de sang aient été transfusés. On a aussi noté l’haptoglobine sérique libre (Hpl). la corrélation entre les changements de concentrations d’hémoglobine ou d’aptoglobine et le nombre de jours de conservation du sang transfusé a été analysée par une analyse de régression simple.Résultats: L’hémoglobine libre a été détectée après 2 000 mL de transfusion. L’HpT et l’Hpl ont baissé après 1 000 mL de transfusion. Le temps total de conservation (jours) du sang transfusé était en corrélation avec les modifications d’HpT (P<0,0001) et d’HpI (P=0,0027), mais non avec les changements d’HbT (P=0,984) ni d’Hbl (P=0,834).Conclusion: Après la transfusion de sang pendant une opération pour trauma, la concentration sérique d’haptoglobine décroît avec une quantité ≥1 000 mL de sang complet transfusé et selon un temps moyen de conservation de 12,2 jours. L’hémoglobine libre est détectée après la transfusion de 2 000 mL tandis que l’Hp T baisse à 1 000 mg·L−1. Les concentrations sériques d’haptoglobine sont en corrélation négative avec le temps de conservation du sang transfusé.

Cerebrovascular carbon dioxide reactivity during general anesthesia : a comparison between sevoflurane and isoflurane

UNLABELLED We compared cerebrovascular carbon dioxide reactivity during the administration of sevoflurane and isoflurane anesthesia by measuring cerebral blood flow velocity (CBFV) as an indirect measurement of cerebral blood flow. Thirty patients, 20-70 yr old, undergoing lower abdominal surgery and without known cerebral or cardiovascular system disease, were randomly assigned to either sevoflurane or isoflurane treatment groups. Anesthesia was induced with thiopental 5 mg/kg IV and maintained with either sevoflurane or isoflurane in 67% nitrous oxide and oxygen. The CBFV and pulsatility index (PI) of the left middle cerebral artery were monitored with transcranial Doppler. The P(ETCO)2 was increased stepwise from 20 to 50 mm Hg by changing the respiratory rate with a constant tidal volume. At every 5-mm Hg stepwise change in P(ETCO)2, CBFV and PI were recorded. CBFV increased with increasing P(ETCO)2. CBFV was significantly smaller in the isoflurane group at P(ETCO)2 = 20-40 mm Hg than in the sevoflurane group. The rate of change of CBFV with changes in CO2 was larger in the isoflurane group than in the sevoflurane group. PI was constant over time and was not different between groups. In conclusion, hypocapnia-induced reduction of intracranial pressure might be more effective during the administration of isoflurane than sevoflurane. IMPLICATIONS Changes in cerebral blood flow caused by the changes of carbon dioxide tension are greater during the administration of isoflurane anesthesia compared with sevoflurane anesthesia. Attempts to decrease intracranial pressure by decreasing carbon dioxide tension may be more successful during isoflurane than sevoflurane anesthesia administration.

The accuracy and precision of four infrared aural canal thermometers during cardiac surgery

Background: Four infrared aural canal thermometers are currently available in Japan: Geniusr̀, Thermoscanr̀, Quickthermor̀, and Thermopitr̀. We therefore tested the hypothesis that each is sufficiently accurate and precise for clinical use.

Is protease inhibitor a choice for the treatment of pre- or mild disseminated intravascular coagulation?

Objective: To investigate the effect of a protease inhibitor, gabexate mesylate, on patients with pre‐ or mild disseminated intravascular coagulation (DIC) in comparison with a control group receiving no anticoagulation therapy. Design: Prospective, randomized, controlled study. Setting: General intensive care unit at a general hospital. Patients: Adult patients (40) with a DIC score between 6 and 8 (pre‐ or mild DIC). Interventions: In 20 patients, gabexate mesylate (2 mg/kg/hr) was administered as 2 mL/hr in saline (treated group) and in another 20 patients, saline (2 mL/hr; control group) was administered during the study (7 days). Measurements and Main Results: The following variables were determined at the time of admission to the intensive care unit before treatment and 1, 3, 5, and 7 days thereafter: platelet count, antithrombin III activity, serum or plasma concentrations of fibrinogen, fibrin degradation product, D‐dimer, fibrin monomer, thrombin‐antithrombin III complex, and plasmin‐plasmin inhibitor complex, prothrombin time ratio, and DIC score. Two patients in the treated group and four in the control group were excluded from the study because they died during the study; therefore, 34 patients were analyzed. The measured variables of coagulation and fibrinolysis were not significantly different between the two groups, except for the D‐dimer on day 3 (the treated group showed a higher concentration). D‐dimer concentration and DIC score went down more quickly in the control group than the treated group, but not significantly. The mortality rate at 1 month was 40% (8 of 20) in the treated group and 35% (7 of 20) in the control group, without any differences between the two groups. Conclusions: In a limited number of patients (n = 34), gabexate mesylate (2 mg/kg/hr) could not inhibit coagulation or fibrinolysis and gabexate mesylate could not improve the DIC score or mortality rate in pre‐ or mild DIC.

The Effects of Age and Gender on the Optimal Premedication Dose of Intramuscular Midazolam

UNLABELLED We conducted a double-blind study on the effects of age and gender on the optimal premedication dose of i.m. midazolam. We randomly divided 100 male and 100 female patients in each of three age groups: A = 20-39 yr, B = 40-59 yr, and C = 60-79 yr (total 600 patients) into five groups according to midazolam dosage: 0.04, 0.06, 0.08, 0.10, and 0.12 mg/kg. Midazolam was injected i.m. with atropine 0.01 mg/kg 15 min before the induction of anesthesia. Blood pressure (BP), heart rate, respiratory rate, oxygen saturation (SpO2), sedation level, tongue root depression, eyelash reflex, and anterograde amnesia were monitored. There were no significant differences between male and female patients in any variables in any age. Decrease of SpO2 and loss of eyelash reflex were seen with midazolam 0.10 mg/kg in Group A, and with 0.08 mg/kg in Group B. In Group C, decreases in BP and SpO2, loss of eyelash reflex, and depression of the tongue root were observed with midazolam 0.06 mg/kg. In conclusion, the optimal doses of i.m. midazolam administered 15 min before the induction of anesthesia in male or female patients were 0.08, 0.06, and 0.04 mg/kg for Groups A, B, and C, respectively. IMPLICATIONS Midazolam is the most widely used preoperative anxiolytic drug. Our purpose was to evaluate the optimal dose of i.m. midazolam that would maximize the desired effects and minimize the side effects in a common clinical setting. Results indicate that age, but not gender, should affect the i.m. midazolam dose selected for premedication.