Tribute to Dr. Takuo Aoyagi, inventor of pulse oximetry.

INTRODUCTION: Dr. Takuo Aoyagi invented pulse oximetry in 1974. Pulse oximeters are widely used worldwide, most recently making headlines during the COVID-19 pandemic. Dr. Aoyagi passed away on April 18, 2020, aware of the significance of his invention, but still actively searching for the theory that would take his invention to new heights. METHOD: Many people who knew Dr. Aoyagi, or knew of him and his invention, agreed to participate in this tribute to his work. The authors, from Japan and around the world, represent all aspects of the development of medical devices, including scientists and engineers, clinicians, academics, business people, and clinical practitioners. RESULTS: While the idea of pulse oximetry originated in Japan, device development lagged in Japan due to a lack of business, clinical, and academic interest. Awareness of the importance of anesthesia safety in the US, due to academic foresight and media attention, in combination with excellence in technological innovation, led to widespread use of pulse oximetry around the world. CONCLUSION: Dr. Aoyagi's final wish was to find a theory of pulse oximetry. We hope this tribute to him and his invention will inspire a new generation of scientists, clinicians, and related organizations to secure the foundation of the theory.

Relationship between regional cerebral blood flow and electrocorticographic activities under sevoflurane and isoflurane anesthesia.

The aims of this study are (1) to assess the effects of volatile anesthetics on regional cerebral blood flow (rCBF) and electrocorticography (ECoG), and (2) to investigate the relationship between rCBF and ECoG influenced by volatile anesthetics. The authors measured rCBF using laser Doppler flowmetry and ECoG simultaneously and continuously from the same cortex during craniotomy, using the specially arranged probe. Patients received intravenous anesthetics with nitrous oxide until craniotomy, and after opening of dura, volatile anesthetic, either isoflurane or sevoflurane, was started and was gradually increased for the measurement. Four of the nine cases (44.4%) of the sevoflurane group showed no change both in rCBF and ECoG. In three cases (33.3%), rCBF increased as the frequency of the paroxysmal activities increased. In two cases (22.2%), decreased rCBF was accompanied by slow waves. In 12 cases of the isoflurane group, no apparent rCBF and ECoG changes were seen, except a case with decreased rCBF and slow waves. This is the first report of simultaneous recordings of regional CBF and neuronal activity under general anesthesia. During sevoflurane and isoflurane anesthesia <2.5 minimum alveolar anesthetic concentration, rCBF is affected by ECoG activities rather than pharmacologic action of inhalational anesthetics.

Anesthetic management of a patient with aortocaval fistula.

Aortocaval fistula is a rare complication of ruptured abdominal aortic aneurysm (AAA), and patients with an aortocaval fistula show multiple symptoms. We report an 87-year-old man who was diagnosed as having an AAA with aortocaval fistula and who developed refractory hypotension after induction of anesthesia. Following a phenylephrine injection for slight hypotension induced by anesthetic induction, he developed severe hypotension and bradycardia, and his skin became cyanotic. Vasopressor agents had no immediate effect on the hypotension, but blood pressure gradually increased in about 30 min with continuous infusion of dopamine and noradrenaline. Transesophageal echocardiography (TEE) showed right ventricle (RV) hypokinesis and massive tricuspid regurgitation (TR). Central venous pressure (CVP) showed a remarkably high value. After the repair of the aortocaval fistula, the hemodynamics became stable, RV motion was improved, TR was reduced, and CVP became normal. Anesthetic management of the repair of an aortocaval fistula is very difficult. The hemodynamics changed dramatically throughout anesthesia in our patient with this disorder, even though low-dose anesthetics were used. For the successful treatment of this disorder, preparation for the operation is required before the induction of anesthesia, and urgent closure of the fistula is necessary after the induction of anesthesia. TEE is a useful tool for monitoring hemodynamics in such patients.

Large volume autologous plasma predonation and retransfusion in orthopedic surgical patients.

BACKGROUND: Intraoperative washed autologous transfusion of the scavenged blood can reduce the deterioration of anemia, even during the operation with a comparatively large blood loss. On the other hand, plasma level can not be collected by this system. The preoperative donation and perioperative retransfusion of autologous plasma may reduce the plasma dilution. PURPOSE: The influence of a large volume plasma predonation and perioperative retransfusion on the plasma protein level was investigated. METHODS: Thirteen patients (63.2 +/- 13.2 yr, 70.3 +/- 12.1 kg) were examined regarding their serum protein (SP), IgG, coagulation systems, colloid osmotic pressure (COP), blood cell count before, just after, 2 h after and 7 days after the donation of 900 ml plasma by plasmapheresis with a simultaneous volume replacement. Twenty surgical patients (52.8 +/- 17.3 yr, 72.6 +/- 16.6 kg, the mean predonated autologous plasma: 2100 ml) with intra- and postoperative retransfusion of autologous plasma were examined perioperatively for SP, IgG, coagulation systems and COP. These parameters were compared with that of the predonated plasma. RESULTS: All data including SP, coagulation and COP, with the exception of IgG, completely recovered within 7 days after preoperative plasmapheresis. Perioperatively, autologous washed blood transfusion system was used. The retransfused volume of autologous predonated plasma was 1740 ml on average. Although about 41 of blood on average was lost perioperatively, only one patient out of 20 patients had to be administered homologous red blood cell transfusion. The levels of most parameters, except for COP, constantly recovered in accordance with the autologous plasma transfusion. Differences in the patterns of improvement were also observed between the parameters. CONCLUSION: A 900 ml plasma predonation can therefore be safely performed with an interval of not less than a week between the last donation and the operation. Autologous plasma retransfusion is thus considered to improve the protein levels.

The lung-to-thorax transverse area ratio at term and near term correlates with survival in isolated congenital diaphragmatic hernia.

OBJECTIVE: The purpose of this study was to determine how well liver position, the lung area-to-head circumference (L/H) ratio, and the lung-to-thorax transverse area (L/T) ratio predicted the need for extra-corporeal membrane oxygenation (ECMO) and survival in fetuses with isolated congenital diaphragmatic hernia (CDH). METHODS: Antenatal records of 25 fetuses with isolated left-sided CDH who were born by cesarean delivery under fetal stabilization at this institution were reviewed. The latest determinations of the L/H and L/T ratios before birth (between 34 and 38 weeks' gestation) were compared on the basis of the cutoff points for mortality: less than 1.0 versus 1.0 or greater for the L/H ratio and 0.08 or less versus greater than 0.08 for the L/T ratio. Outcome measures assessed were survival (discharge to home) and the need for ECMO. RESULTS: Overall survival was 64% (16/25). Postnatal survival in fetuses with an L/T ratio of 0.08 or less was statistically lower than in those with an L/T ratio of greater than 0.08 (33% versus 81%; P = .0308). The percentage requiring ECMO in the group with an L/T ratio of 0.08 or less was also higher than that of the group with an L/T ratio of greater than 0.08, but the difference was not statistically significant (67% versus 25%; P = .0872). Neither the L/H ratio nor herniation of the fetal liver into the chest affected survival or the need for ECMO. CONCLUSIONS: In fetuses with isolated CDH at term or near term, the L/T ratio may be a better predictor of outcome than the L/H ratio or liver herniation.

Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation.

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient's pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.

Evaluation of finger and forehead pulse oximeters during mild hypothermic cardiopulmonary bypass.

OBJECTIVE: The purpose of this study was to examine and compare the four combination of pulse oximeters (POs) and monitoring sites, the Nihon Kohden BSS-9800 (N), the Masimo SET Radical (M), the Nellcor N550 D-25 (N-D) and the Nellcor N550 Max-Fast (N-MF) in patients with peripheral hypoperfusion. METHODS: About 20 adult patients undergoing cardiac surgery using mild hypothermic cardiopulmonary bypass (CPB) were studied prospectively. PO sensors were applied on fingers in N, M and N-D, while on the forehead in N-MF. RESULTS: PO failure was defined as failure to show no SpO2 value or incorrect SpO2 values. PO failure occurred in 12 patients with N, ten patients with M, four patients with N-D and ten patients with N-MF, respectively (p < 0.05 N-D vs. N, M, N-MF). The duration of PO failure was 19 +/- 30% of aortic cross-clamping with N, 29 +/- 33% with M, 10 +/- 26% with N-D and 43 +/- 57% with N-MF, respectively (p < 0.05 N-D vs. M and N-MF). CONCLUSIONS: The results suggested that N-D is most useful among four combinations of POs and monitoring sites tested in this study for monitoring SpO2 during hypoperfusion. The superiority of N-MF during hypoperfusion was not evident in the present study.

[Anesthesia for a patient with xeroderma pigmentosum].

A 23-year-old man with xeroderma pigmentosum underwent laparoscopic cholecystectomy. He experienced transient worsening of the neurological symptom after anesthesia with volatile agents in the previous surgery. Because volatile anesthetics potentially cause genotoxic effects in patients with xeroderma pigmentosum, this time we chose total ir.travenous anesthesia (TIVA). The intraoperative management and the post-operative course were uneventful this time. From these two anesthesia experiences in one patient, we suggest that TIVA is more appropriate than anesthesia with volatile agents as a method for general anesthesia for xeroderma pigmentosum patients. Minimum usage of muscle relaxants under the monitoring of neuromuscular blockade is also recommended, since xeroderma pigmentosum patients are sensitive to muscle relaxants due to the neuronal dysfunction and muscle

Prognosis of patient with cardiopulmonary arrest transported to Kyushu University Hospital.

Three hundreds and sixty six patients with out-of-hospital cardiopulmonary arrest, transported to the Kyushu University Hospital from 2000 to 2006, were examined using the Utstein style in witnessed cardiogenic cardiopulmonary arrest patients. Also, we examined the influence on prognosis due to the difference in the treatment of airway control in out-of-hospital settings. Nineteen patients out of 78 witnessed cardiogenic out-of-hospital cardiopulmonary arrest patients were discharged alive and 11 were with a good prognosis. The number of cases where an initial electrocardiographic complex showed ventricular fibrillation or pulseless ventricular tachycardia was higher than formerly reported in Japan and was equal to the incidence reported in Europe and America. In addition, the survival discharge rate of patients with the ventricular fibrillation or pulseless ventricular tachycardia was higher than that previously reported in Japan and was similar to European and American results. Manual airway maintenance using a bag valve mask was more successful in terms of the survival discharge rate compared to the use of advanced airway devices. By the time course, collapse to cardiopulmonary resuscitation interval, collapse to initial defibrillation interval and collapse to the return of spontaneous circulation interval were shorter in the group discharged with a good prognosis, especially in the witnessed ventricular fibrillation or pulseless ventricular tachycardia patients corresponding to former reports. Most patients with a good prognosis resuscitated before arrival at the hospital. These results suggest the prehospital treatment is the critical point other than in-hospital treatment.

Plasmin induces endothelium-dependent nitric oxide-mediated relaxation in the porcine coronary artery.

OBJECTIVE: Plasmin is a key enzyme in fibrinolysis. We attempted to determine the possible role of plasmin in the regulation of vascular tone, while also investigating the mechanism of plasmin-induced vasorelaxation. METHODS AND RESULTS: In porcine coronary artery, plasmin induced an endothelium-dependent relaxation. This relaxing effect was mostly abolished by a proteinase inhibitor, a plasmin inhibitor, or a nitric oxide (NO) synthase inhibitor. The preceding stimulation with plasmin significantly inhibited the subsequent relaxation induced by thrombin but not that induced by proteinase-activated receptor-1-activating peptide. The relaxation induced by trypsin and substance P remained unaffected by the preceding plasmin stimulation. The pretreatment with plasmin, thrombin, or trypsin significantly attenuated the plasmin-induced relaxation. In porcine coronary artery endothelial cells (PCAECs) and human umbilical vein endothelial cells (HUVECs), plasmin induced a transient elevation in the cytosolic Ca2+ concentrations ([Ca2+]i). The preceding stimulation with plasmin inhibited the subsequent [Ca2+]i elevation induced by thrombin but not that induced by trypsin. In PCAECs, plasmin concentration-dependently induced NO production. CONCLUSIONS: The present study demonstrated, for the first time, that plasmin induced an endothelium-dependent NO-mediated relaxation in the porcine coronary artery, while also showing plasmin to specifically inactivate the thrombin receptor.

Rapid and random turnover of mitochondrial DNA in rat hepatocytes of primary culture.

It is known that mitochondrial DNA (mtDNA) replication is independent of the cell cycle. Even in post-mitotic cells in which nuclear DNA replication has ceased, mtDNA is believed to still be replicating. Here, we investigated the turnover rate of mtDNA in primary rat hepatocytes, which are quiescent cells. Southwestern blot analysis using 5-bromo-2'-deoxyuridine (BrdU) was employed to estimate the activity of full-length mtDNA replication and to determine efficient doses of replication inhibitors. Southern blot analysis showed that a two-day treatment with 20mM 2',3'-dideoxycytidine and 0.2mug/ml ethidium bromide caused a 37% reduction in the amount of mtDNA, indicating that the hepatocytes had a considerably high rate of turnover of mtDNA. Further, pulse-chase analysis using Southwestern analysis showed that the amount of newly synthesized mtDNA labeled with BrdU declined to 60% of the basal level within two days. Because the rate of reduction of the new mtDNA was very similar to the overall turnover rate described above, it appears that degrading mtDNA molecules were randomly chosen. Thus, we demonstrated that there is highly active and random turnover of mtDNA in hepatocytes.

[Dexmedetomidine].

Dexmedetomidine, a potent and highly selective alpha2-agonist, provides a unique "conscious sedation" (patients appear to be asleep, but are readily roused), analgesia, without respiratory depression. In order to provide a comfortable sedation to the ICU patients, careful evaluation of sedation and analgesia level, and the consistent treatment by medical teams are necessary. We may expect the usefulness of dexmedetomidine in the settings other than the ICU, from its pharmacological properties. Clinical applications of dexmedetomidine for several procedures such as awake craniotomy, fiberoptic tracheal intubation, or MRI examination have been reported, suggesting its usefulness and problems. The major problem with dexmedetomidine is its hemodynamic effects. Because this drug often causes hypotension, hypertension and bradycardia, it should be used under the control by skilled medical teams.

Noninvasive assessment of left ventricular pressure-area relationship using transesophageal echocardiography and tonometry during cardiac and abdominal aortic surgery.

PURPOSE: The purpose of this study was to noninvasively evaluate intraoperative left ventricular (LV) performance by an online pressure-area relationship using transesophageal echocardiography (TEE) and tonometry. METHODS: In study 1, LV pressure with a micromanometer catheter, LV cross-sectional area with TEE, direct radial pressure, and tonometric arterial pressure were simultaneously recorded in 5 patients (10 measurements) undergoing cardiac surgery. End-systolic elastance (E'es) was determined from pressure-area loops during inferior vena caval (IVC) occlusion. In study 2, in 16 patients undergoing repair of abdominal aortic aneurysm, LV performance (E'es; effective arterial load, E'a, and LV end-diastolic area, LV-EDA) was examined by noninvasive assessment of pressure-area loops using TEE and tonometry at aortic cross-clamping and unclamping. RESULTS: E'es by tonometric arterial pressure closely correlated with E'es by LV pressure (r = 0.92) in study 1. E'es at aortic clamping were not significantly different from those at unclamping. The clamping increased LV-EDA and E'a by approximately 13% and 44%, and the unclamping significantly decreased by 9% and 22%, respectively. CONCLUSION: Our results demonstrated that online tonometric arterial pressure and LV area measured by automated border detection (ABD) of TEE might be used to calculate E'es to estimate LV contractility and allow the estimation of LV performance during aortic clamping and unclamping.

Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.

The endothelium synthesizes and releases several vasodilator substances, including vasodilator prostaglandins, NO, and EDHF. NO-mediated relaxations are reduced by various risk factors, such as diabetes mellitus and hypercholesterolemia. However, it remains to be elucidated whether EDHF-mediated relaxations also are reduced by those factors and their combination. In this study, we addressed this point in mice. We used small mesenteric arteries from control, diabetic (streptozotocin-induced), apolipoprotein-E-deficient (ApoE-/-), and diabetic ApoE-/- mice. In control mice, endothelium-dependent relaxations to acetylcholine were largely mediated by EDHF. This EDHF-mediated component was slightly reduced in diabetic mice, preserved in ApoE-/- mice, and markedly reduced in diabetic ApoE-/- mice with an increase in NO-mediated component and a negative contribution of indomethacin-sensitive endothelium-derived contracting factor (EDCF). Endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of calcium-activated K channels, were attenuated in ApoE-/- and diabetic ApoE-/- mice. Endothelium-dependent hyperpolarizations were significantly reduced in diabetic mice, preserved in ApoE-/- mice, and again markedly reduced in diabetic ApoE-/- mice. These results indicate that hypercholesterolemia alone minimally affects the EDHF-mediated relaxations, and diabetes mellitus significantly attenuated the responses, whereas their combination markedly attenuates the responses with a compensatory involvement of NO and a negative contribution of EDCF.

Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries.

The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have identified hydrogen peroxide (H2O2) as an EDHF in mouse and human mesenteric arteries and porcine coronary microvessels. We also have recently demonstrated that Cu,Zn-SOD plays an important role in EDHF synthesis in mouse mesenteric arteries. However, it remains to be determined whether SOD also plays an important role in EDHF-mediated responses of human arteries. In this study, we addressed this point in human mesenteric arteries. We used small mesenteric arteries of patients who underwent gastrectomy operations. Isometric tensions and membrane potentials were recorded in the presence of indomethacin and N-nitro-L-arginine to inhibit the synthesis of prostacyclin and NO, respectively. Pretreatment with Tiron, a cell-permeable SOD-mimetic, significantly enhanced the EDHF-mediated relaxations and hyperpolarizations to bradykinin, and this effect was abolished by catalase, indicating that this enhancing effect was achieved by H2O2. By contrast, Tiron did not affect endothelium-independent relaxations, indicating that the enhancing effect of Tiron is not caused by the enhancement of vascular smooth muscle responses. These results indicate that SOD plays an important role in EDHF-mediated relaxations and hyperpolarizations of human mesenteric arteries.

[Changes in serum Na+ and blood hemoglobin levels during three types of transurethral procedures for the treatment of benign prostatic hypertrophy].

BACKGROUND: Transurethral holmium YAG laser resection of the prostate (HoLR-P) and transurethral electrovaporization of the prostate (TUV-P) have recently received increasing attention as an effective minimally invasive approach for the treatment of prostatic hypertrophy. However, less information is available regarding the intraoperative changes in the serum Na+ and blood hemoglobin levels during either HoLR-P or TUV-P. METHODS: Intraoperative changes in serum Na+ and blood hemoglobin levels were investigated in 17 patients undergoing transurethral resection of the prostate (TUR-P, n = 7), HoLR-P (n = 7) or TUV-P (n = 3). The 3% D-sorbitol solution was used as the irrigating fluid in all the patients. RESULTS: In three patients, severe hyponatremia (118-123 mEq x l(-1)) developed abruptly (< or = 15 min) at various time points during TUR-P with (n = 1) or without (n = 2) cystostomy. However, no clinical symptoms were observed after development of the hyponatremia in those awake patients. No large (> 10 mEq x l(-1)) decreases in the Na+ level were observed in any of the patients undergoing HoLR-P or TUV-P. In patients undergoing TUR-P and HoLR-P, percent changes in serum Na+ level significantly correlated with those in blood hemoglobin level, but not with the resection time; the slopes were significantly larger than unity. CONCLUSIONS: The TUR syndrome is less likely to occur during HoLR-P or TUV-P. During TUR-P, the onset of severe hyponatremia appears to be unpredictable, and may not necessarily be accompanied by clinical symptoms. Frequent measurements of the serum Na+ level appear essential for early detection of severe hyponatremia.

Inactivation of protease-activated receptor-1 by proteolytic removal of the ligand region in vascular endothelial cells.

Proteolysis plays an important role in inactivating protease-activated receptor-1 (PAR1). We aimed to determine the cleavage site(s) responsive for the proteolytic inactivation of PAR1 in human umbilical vein endothelial cells. Fura-2 fluorometry revealed that the preceding stimulation with trypsin abolished the subsequent [Ca(2+)](i) response to thrombin, while the responses to PAR1-activating peptides remained intact. On the other hand, thrombin had no effect on the subsequent response to trypsin. The immunostaining with antibodies against the residues 35-46 (SPAN12) and 51-64 (WEDE15) revealed the broad boundaries of cleavage. Trypsin removed both epitopes from the cell surface within 3 min, while thrombin removed the epitope of SPAN12. The longer incubation with thrombin removed the epitope of WEDE15. However, PAR1-activating peptides thereafter induced an attenuated but significant elevation of [Ca(2+)](i). Not only the receptor internalization as observed with a confocal microscope, but also an additional cleavage was thus suggested to contribute to the thrombin-induced removal of the epitope of WEDE15. The analyses of the PAR1 mutants identified three cleavage sites for trypsin; residues 41-42, 70-71 and 82-83. The cleavage at the latter two sites was suggested to dominate that at the former, and thus remove the ligand region (residues 42-47). The inactivation of PAR1 due to proteolytic removal of the ligand region may contribute not only to the inactivation of PAR1 by proteases such as trypsin, but also to the termination of the intracellular signaling initiated by thrombin in the vascular endothelial cells.

Changes in body temperature during profound hypothermic cardiopulmonary bypass in adult patients undergoing aortic arch reconstruction.

PURPOSE: Our aim was to characterize changes in body temperatures during profound hypothermic cardiopulmonary bypass (CPB) conducted with the sternum opened. METHODS: In ten adult patients who underwent profound hypothermic (< 20 degrees C) CPB for aortic arch reconstruction, pulmonary arterial temperature (PAT), nasopharyngeal temperature (NPT), forehead deep-tissue temperature (FHT), and urinary bladder temperature (UBT) were recorded every 1 min throughout the surgery. In addition, the CPB venous line temperature (CPBT), a reasonable indicator of mixed venous blood temperature during CPB and believed to best reflect core temperature during stabilized hypothermia on CPB, was recorded during the period of total CPB. RESULTS: PAT began to change immediately after the start of cooling or rewarming, closely matching the CPBT ( r = 0.98). During either situation, the other four temperatures lagged behind PAT ( P < 0.05); however, NPT followed PAT more closely than the other three temperatures ( P < 0.05). During stabilized hypothermia, PAT, NPT, and FHT, but not UBT, closely matched the CPBT, with gradients of less than 0.5 degrees C. CONCLUSION: During induction of profound hypothermia and its reversal on total CPB with the heart in situ, a PA catheter thermistor, presumably because of its placement immediately behind the superior vena cava, would provide a reliable measure of the mixed venous blood temperature. During stabilized profound hypothermia, PAT, NPT, and FHT, but not UBT, serve as a reliable index of core temperature.