Shinhiro Takeda

Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats

BackgroundUnderlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists. MethodsNewborn rat brainstem–spinal cord preparations were used and superfused with &mgr;-, &kgr;-, and &dgr;-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory). ResultsMu- and &kgr;-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of &mgr;- and &kgr;-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by &mgr;- and &kgr;-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses. ConclusionsMu- and &kgr;-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.

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

The efficacy of dexmedetomidine in patients with noninvasive ventilation: a preliminary study.

BACKGROUND: Agitation is associated with failure of noninvasive ventilation (NIV). We investigated the effect of dexmedetomidine in patients with NIV. METHODS: This was a prospective clinical investigation in an intensive care unit. Dexmedetomidine was infused in 10 patients in whom NIV was difficult because of agitation. RESULTS: Ramsay and Richmond Agitation-Sedation Scale scores were maintained at 2.94 ± 0.94 and −1.23 ± 1.30, respectively. All patients were successfully weaned from NIV, and the respiratory state was not worsened. CONCLUSION: This study shows that dexmedetomidine is an effective sedative drug for patients with NIV.

A prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) reduces hyperalgesia, allodynia, and c-fos gene expression in rats with chronic nerve constriction.

Chronic constriction injury (CCI) of the sciatic nerve in rats induces persistent mechanical hyperalgesia and allodynia. CCI is widely known as a model of neuropathic pain, and many studies using this model have been reported. Recently, c-fos has been used as a neural marker of pain, and various studies have assessed the relationship between hyperalgesia and c-fos expression in the lumbar spinal cord. In this study, we examined the role of a prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) in a rat CCI model. EP1 receptor antagonist (EP1-ra) oral administration from day 8 to day 14 significantly reduced hyperalgesia and allodynia in the three pain tests on day 15. EP1-ra treatment from day 8 to 14 also reduced c-fos-positive cells in laminae I-II, III-IV, and V-X compared with saline treatment. A single dose of EP1-ra treatment on day 8 significantly reduced hyperalgesia and allodynia at 1 h and 2 h after administration, but the efficacy was not observed at 24 h. We conclude that EP1-ra treatment may be useful for hyperalgesia and allodynia and that EP1 receptor mechanisms are involved in the maintenance of c-fos gene expression induced by nerve injury.

Effects of ulinastatin treatment on the cardiopulmonary bypass-induced hemodynamic instability and pulmonary dysfunction.

Objective:To examine the association between decreased release of proinflammatory cytokines in response to urinary trypsin inhibitor pretreatment and decreased myocardial and lung injury after cardiopulmonary bypass. Design:A prospective, randomized, double-blind study. Setting:University hospital. Subjects:Thirty patients on cardiopulmonary bypass undergoing coronary artery bypass grafting. Interventions:Patients received 5000 units/kg intravenous urinary trypsin inhibitor (n = 15) or 0.9% saline (control, n = 15) immediately before aortic cannulation for cardiopulmonary bypass. Measurement and Main Results:Neutrophil elastase, tumor necrosis factor-&agr;, interleukin-6, and interleukin-8 were measured after intubation (T1), immediately before aortic cannulation (T2), after separation from cardiopulmonary bypass (T3), at the end of surgery (T4), and on postoperative days 1 (T5), 3 (T6), and 5 (T7). Simultaneous hematocrit values were obtained at all sample times. Isoenzyme of creatine kinase with muscle and brain subunits, troponin-T, and myosin light chain I were also measured. Various hemodynamic and pulmonary data were obtained perioperatively. Levels of neutrophil elastase and cytokines were corrected for hemodilution. Interleukin-6 and interleukin-8 levels were lower at T3 and T4 in the urinary trypsin inhibitor group than in the control group. Stroke volume index was significantly decreased in the control group at T3, and statistical difference was found between groups at T3 (p < .01). Respiratory index and intrapulmonary shunt were significantly higher in the control group than in the urinary trypsin inhibitor group at T3. Changes in respiratory index and intrapulmonary shunt correlated with interleukin-8 levels at T3 (r2 = .52, p < 00001; r2 = .37, p < 0001, respectively) and T4 (r2 = .44, p < .001; r2 = .24, p < .05, respectively). Neutrophil elastase levels and cardiac marker responses to coronary artery bypass grafting surgery were similar in both groups. Conclusions:Prepump administration of urinary trypsin inhibitor attenuates the elevation of interleukin-6 and interleukin-8 release immediately after cardiopulmonary bypass.

The effect of nasal continuous positive airway pressure on plasma endothelin-1 concentrations in patients with severe cardiogenic pulmonary edema.

We investigated the effects of nasal continuous positive airway pressure (CPAP) on plasma endothelin-1 (ET-1) concentrations in patients with cardiogenic pulmonary edema. Thirty patients were randomly assigned to two groups: 15 patients who received oxygen plus nasal CPAP (CPAP group), and 15 patients who received only oxygen by face mask (oxygen group). The heart rate and the mean pulmonary artery pressure decreased significantly in the CPAP group. The PaO2/fraction of inspired oxygen (FIO2) ratio increased in the CPAP group (163 +/- 70 to 332 +/- 104, P < 0.01) after 6 h and was significantly higher than that in the oxygen group. Arterial plasma ET-1 concentrations decreased from 6.2 +/- 2.0 pg/mL to 4.8 +/- 1.7 pg/mL (P < 0.05) after 6 h and to 3.3 +/- 0.7 pg/mL (P < 0.01) after 24 h in the CPAP group. Arterial plasma ET-1 concentrations in the CPAP group compared with the oxygen group were significantly lower at 24 h. There was a correlation between the arterial plasma ET-1 concentrations and mean pulmonary artery pressure (r = 0.62, P < 0.001), and PaO2/FIO2 (r = -0.46, P < 0.01). Nasal CPAP led to an early decrease in plasma ET-1 concentrations, and improvement in oxygenation and hemodynamics. (Anesth Analg 1997;84:1091-6)

Clinical role and efficacy of landiolol in the intensive care unit

Beta-adrenergic receptor blockers have proved to be effective for the management of various cardiovascular diseases and the prevention of perioperative cardiac events and cerebrovascular accidents. Landiolol is a short-acting beta-blocker, with high beta 1-selectivity and a short duration of action. We thought landiolol was valuable and suitable for intensive care unit (ICU) patients, and conducted a retrospective study. The records of 80 patients (58 post-surgical patients; group S and 22 internal medicine patients; group IM) were reviewed. Thirty-seven (64%) of the group S patients were post-coronary artery bypass graft surgery, and the IM group consisted mostly of patients with acute myocardial infarction. The most common indication for landiolol in group S was the prevention of myocardial ischemia (50%), and in group IM, it was atrial fibrillation (45%). The median infusion rate of landiolol was 5 μg·kg−1·min−1 and the median infusion time was 2 days. Twenty-six patients were continued on oral beta-adrenergic receptor blockers. Landiolol reduced heart rate significantly without reducing blood pressure, and stabilized hemodynamics. We confirmed that landiolol is valuable as a bridge to starting oral beta-adrenergic receptor blockers and as an anti-arrhythmic agent, and that it is suitable for ICU patients due to its high beta 1-selectivity and rapid onset and offset of action.

Factors predicting successful noninvasive ventilation in acute lung injury

PurposeNoninvasive ventilation (NIV) has been successfully used to treat various forms of acute respiratory failure. It remains unclear whether NIV has potential as an effective therapeutic method in patients with acute lung injury (ALI). The aims of this study were to determine factors predicting the need for endotracheal intubation in ALI patients treated with NIV, and to promote the selection of patients suitable for NIV.MethodsWe conducted a retrospective study of all patients admitted to the intensive care unit (ICU) of the Nippon Medical School Hospital from 2000 to 2006 with a diagnosis of ALI, in whom NIV was initiated.ResultsA total of 47 patients with ALI received NIV, and 33 patients (70%) successfully avoided endotracheal intubation. Patients who required endotracheal intubation had a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and a significantly higher Simplified Acute Physiology Score (SAPS) II, and a significantly lower arterial pH. The respiratory rate decreased significantly within 1 h of starting NIV only in patients successfully treated with NIV. An APACHE II score of more than 17 (P = 0.022) and a respiratory rate of more than 25 breaths·min−1 after 1 h of NIV (P = 0.024) were independent factors associated with the need for endotracheal intubation. Patients who avoided endotracheal intubation had a significantly lower ICU mortality rate and in-hospital mortality rate than patients who required endotracheal intubation.ConclusionWe determined an APACHE II score of more than 17 and a respiratory rate of more than 25 breaths·min−1 after 1 h of NIV as factors predicting the need for endotracheal intubation in ALI patients treated with NIV.

Hypercytokinemia with 2009 pandemic H1N1 (pH1N1) influenza successfully treated with polymyxin B-immobilized fiber column hemoperfusion

In September 2009, a 16-year-old female with no medical history developed fever, general fatigue, and diarrhea. A rapid diagnosis kit at a local clinic showed type A influenza. She was given 10 mg zanamivir inhalation, twice daily. The following day, her body temperature rose to 41.7 C and she experienced respiratory distress. She was transported to our hospital by ambulance. On arrival, her blood pressure was 90/ 40 mmHg, heart rate 150/min, and respiratory rate 35/min. She was administered a large dose of crystalloid fluid and norepinephrine (0.3 lg/kg/min). Mechanical ventilation with endotracheal intubation was begun. Purulent sputum removed by suction contained Gram-positive cocci on a Gram-stained smear. Cultures of blood, urine, and stool testing for various pathogens were negative. Mechanical ventilation was performed in pressure control mode with PaO2/FiO2 (P/F) ratio of 148. Thereafter, a recruitment maneuver was performed, switching to airway pressure release ventilation (APRV) mode. P/F ratio temporarily improved to 224, but then deteriorated to 165. Oseltamivir (150 mg/day), sivelestat sodium hydrate (300 mg/day), and antibiotics (initially ampicillin/ sulbactam 6 g/day) were administered. On day 2, complicated by disseminated intravascular coagulation, no improvement in respiratory status was observed, prompting an increase in oseltamivir dosage to 300 mg/day. Type A influenza was confirmed as 2009 pandemic H1N1 (pH1N1) virus by polymerase chain reaction (PCR). On day 3, methicillin-resistant Staphylococcus aureus (MRSA) was identified in the sputum collected immediately after intubation. Antibiotics were changed to linezolid (12 g/day) plus clindamycin (1,800 mg/day) for MRSA. Serum cytokine levels were highly elevated (Fig. 1). We considered that the severe respiratory failure might be related to hypercytokinemia caused by pH1N1 and MRSA infection. With no improvement in oxygenation, polymyxin B-immobilized fiber column (PMX) hemoperfusion was begun in an attempt to reduce the inflammatory mediators and improve oxygenation. Oxygenation gradually improved; after 1 h, the P/F ratio increased from 144 to 184, and after 8 h to 308. PMX hemoperfusion was performed for 14 h; following cessation, oxygenation declined (P/F ratio 220). On days 4 and 5, PMX hemoperfusion was planned for 18 h on each day, and the P/F ratio increased to 407. Serum inflammatory mediators decreased to normal levels after the PMX treatments. She was extubated and discharged from the hospital. Respiratory failure accounts for a large proportion of pH1N1-related deaths. In influenza A (H5N1) virus infection, hypercytokinemia was observed in fatal cases [1]. We postulated that hypercytokinemia led to respiratory failure. A fatal case of

Postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting or cardiac valve surgery: intraoperative use of landiolol

BackgroundLandiolol hydrochloride is a new β-adrenergic blocker with a pharmacological profile that suggests it can be administered safely to patients who have sinus tachycardia or tachyarrhythmia and who require heart rate reduction. This study aimed to investigate whether intraoperative administration of landiolol could reduce the incidence of atrial fibrillation (AF) after cardiac surgery.MethodsOf the 200 consecutive patients whose records could be retrieved between October 2006 and September 2007, we retrospectively reviewed a total of 105 patients who met the inclusion criteria: no previous permanent/persistent AF, no permanent pacemaker, no renal insufficiency requiring dialysis, and no reactive airway disease, etc. Landiolol infusion was started after surgery had commenced, at an infusion rate of 1 μg/kg/min, titrated upward in 3–5 μg/kg/min increments. The patients were divided into 2 groups: those who received intraoperative β-blocker therapy with landiolol (landiolol group) and those who did not receive any β-blockers during surgery (control group). An unpaired t test and Fisher’s exact test were used to compare between-group differences in mean values and categorical data, respectively.ResultsSeventeen of the 105 patients (16.2%) developed postoperative atrial fibrillation: 5/57 (8.8%) in the landiolol group and 12/48 (25%) in the control group. There was a significant difference between the two groups (P=0.03). The incidence of AF after valve surgery and off-pump coronary artery bypass grafting was lower in the landiolol group, although the difference between the groups was not statistically significant.ConclusionsOur retrospective review demonstrated a marked reduction of postoperative AF in those who received landiolol intraoperatively. A prospective study of intraoperative landiolol for preventing postoperative atrial fibrillation is warranted.