Tsukasa Tajima

Hyperbaric oxygen therapy accelerates neurologic recovery after 15-minute complete global cerebral ischemia in dogs

Background and MethodsAlthough hyperbaric oxygen therapy is clinically used for the treatment of several types of ischemic brain injury, few basic animal studies are available that provide a rationale for this therapy for complete global brain ischemia. Therefore, we investigated the effect of hyperbaric oxygen therapy on neurologic recovery after 15-min complete global cerebral ischemia in a canine model. Complete global ischemia was induced in 19 dogs by occlusion of the ascending aorta and the caval veins. Nine dogs were randomized to treatment with hyperbaric oxygenation (3 atmospheres absolute, 100% oxygen for 1 hr) at 3, 24, and 29 hrs after ischemia under spontaneous respiration, while the other ten dogs served as the control group without hyperbaric oxygen therapy (group C). Neurologic recovery was evaluated based on the electroencephalogram (EEC) activity score (1 = normal; 5 = isoelectric) and the neurologic recovery score (100 = normal; 0 = brain death) over a 14-day postischemic period. ResultsThe survival rates were 3/10 (30%) in the control group vs. 7/9 (78%) in the group treated with hyperbaric oxygen (p < .05). Over the 14-day postischemic period, the best (lowest) EEG scores of each dog were significantly (1.7 ± 0.2 vs. 2.9 ± 0.3; mean ± SE, p < .01) lower in the hyperbaric oxygen-treated group. The best neurologic recovery scores of each dog were significantly (69 ± 6 vs. 48 ± 5; mean ± SE, p < .05) higher in the treated animals. The number of dogs that recovered to a neurologic recovery score of >65 (assessed as a slight disability) were 1/10 in the control group and 6/9 in the group treated with hyperbaric oxygen (p < .02). ConclusionsHyperbaric oxygen therapy performed in the early postischemic period accelerated neurologic recovery and improved the survival rate in dogs after 15-mins of complete global cerebral ischemia.

Survival prediction for advanced cancer patients in the real world: A comparison of the Palliative Prognostic Score, Delirium-Palliative Prognostic Score, Palliative Prognostic Index and modified Prognosis in Palliative Care Study predictor model

PURPOSE The aim of this study was to investigate the feasibility and accuracy of the Palliative Prognostic Score (PaP score), Delirium-Palliative Prognostic Score (D-PaP score), Palliative Prognostic Index (PPI) and modified Prognosis in Palliative Care Study predictor model (PiPS model). PATIENTS AND METHODS This multicentre prospective cohort study involved 58 palliative care services, including 19 hospital palliative care teams, 16 palliative care units and 23 home palliative care services, in Japan from September 2012 to April 2014. Analyses were performed involving four patient groups: those treated by palliative care teams, those in palliative care units, those at home and those receiving chemotherapy. RESULTS We recruited 2426 participants, and 2361 patients were finally analysed. Risk groups based on these instruments successfully identified patients with different survival profiles in all groups. The feasibility of PPI and modified PiPS-A was more than 90% in all groups, followed by PaP and D-PaP scores; modified PiPS-B had the lowest feasibility. The accuracy of prognostic scores was ⩾69% in all groups and the difference was within 13%, while c-statistics were significantly lower with the PPI than PaP and D-PaP scores. CONCLUSION The PaP score, D-PaP score, PPI and modified PiPS model provided distinct survival groups for patients in the three palliative care settings and those receiving chemotherapy. The PPI seems to be suitable for routine clinical use for situations where rough estimates of prognosis are sufficient and/or patients do not want invasive procedure. If clinicians can address more items, the modified PiPS-A would be a non-invasive alternative. In cases where blood samples are available or those requiring more accurate prediction, the PaP and D-PaP scores and modified PiPS-B would be more appropriate.

Effect of continuous deep sedation on survival in patients with advanced cancer (J-Proval): a propensity score-weighted analysis of a prospective cohort study

BACKGROUND Continuous deep sedation (CDS) before death is a form of palliative sedation therapy that has become a focus of strong debate, especially with respect to whether it shortens survival. We aimed to examine whether CDS shortens patient survival using the propensity score-weighting method, and to explore the effect of artificial hydration during CDS on survival. METHODS This study was a secondary analysis of a large multicentre prospective cohort study that recruited and followed up patients between Sept 3, 2012, and April 30, 2014, from 58 palliative care institutions across Japan, including hospital palliative care settings, inpatient palliative care units, and home-based palliative care services. Adult patients (aged ≥ 20 years) with advanced cancer who received care through the participating palliative care services were eligible for this secondary analysis. Patients with missing data for outcome variables or who lived for more than 180 days were excluded. We compared survival after enrolment between patients who did and did not receive CDS. We used a propensity score-weighting method to control for patient characteristics, disease status, and symptom burden at enrolment. FINDINGS Of 2426 enrolled patients with advanced cancer, we excluded 289 (12%) for living longer than 180 days and 310 (13%) with missing data, leaving an analysis population of 1827 patients. 269 (15%) of 1827 patients received CDS. Unweighted median survival was 27 days (95% CI 22-30) in the CDS group and 26 days (24-27) in the no CDS group (median difference -1 day [95% CI -5 to 4]; HR 0·92 [95% CI 0·81-1·05]; log-rank p=0·20). After propensity-score weighting, these values were 22 days (95% CI 21-24) and 26 days (24-27), respectively (median difference -1 day [95% CI -6 to 4]; HR 1·01 [95% CI 0·87-1·17]; log-rank p=0·91). Age (p(interaction)=0·67), sex (p(interaction)=0·26), performance status (p(interaction)=0·90), and volume of artificial hydration (p(interaction)=0·14) did not have an effect modification on the association between sedation and survival, although care setting did have a significant effect modification (p(interaction)=0·021). INTERPRETATION CDS does not seem to be associated with a measurable shortening of life in patients with advanced cancer cared for by specialised palliative care services, and could be considered a viable option for palliative care in this setting. FUNDING Japanese National Cancer Center Research and Development Fund.

Surprise Questions for Survival Prediction in Patients With Advanced Cancer: A Multicenter Prospective Cohort Study

BACKGROUND Predicting the short-term survival in cancer patients is an important issue for patients, family, and oncologists. Although the prognostic accuracy of the surprise question has value in 1-year mortality for cancer patients, the prognostic value for short-term survival has not been formally assessed. The primary aim of the present study was to assess the prognostic value of the surprise question for 7-day and 30-day survival in patients with advanced cancer. PATIENTS AND METHODS The present multicenter prospective cohort study was conducted in Japan from September 2012 through April 2014, involving 16 palliative care units, 19 hospital-based palliative care teams, and 23 home-based palliative care services. RESULTS We recruited 2,425 patients and included 2,361 for analysis: 912 from hospital-based palliative care teams, 895 from hospital palliative care units, and 554 from home-based palliative care services. The sensitivity, specificity, positive predictive value, and negative predictive value of the 7-day survival surprise question were 84.7% (95% confidence interval [CI], 80.7%-88.0%), 68.0% (95% CI, 67.3%-68.5%), 30.3% (95% CI, 28.9%-31.5%), and 96.4% (95% CI, 95.5%-97.2%), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the 30-day surprise question were 95.6% (95% CI, 94.4%-96.6%), 37.0% (95% CI, 35.9%-37.9%), 57.6% (95% CI, 56.8%-58.2%), and 90.4% (95% CI, 87.7%-92.6%), respectively. CONCLUSION Surprise questions are useful for screening patients for short survival. However, the high false-positive rates do not allow clinicians to provide definitive prognosis prediction. IMPLICATIONS FOR PRACTICE The findings of this study indicate that clinicians can screen patients for 7- or 30-day survival using surprise questions with 90% or more sensitivity. Clinicians cannot provide accurate prognosis estimation, and all patients will not always die within the defined periods. The screened patients can be regarded as the subjects to be prepared for approaching death, and proactive discussion would be useful for such patients.

Treatment Efficacy of Neural Blockade in Specialized Palliative Care Services in Japan: A Multicenter Audit Survey

More than 85% of cancer-related pain is pharmacologically controllable, but some patients require interventional treatments. Although audit assessment of these interventions is of importance to clarify the types of patients likely to receive benefits, there have been no multicenter studies in Japan. The primary aims of this study were (1) to clarify the frequency of neural blockade in certified palliative care units and palliative care teams, (2) determine the efficacy of interventions, and (3) explore the predictors of successful or unsuccessful intervention. All patients who received neural blockade were consecutively recruited from seven certified palliative care units and five hospital palliative care teams in Japan. Primary responsible physicians reported pain intensity on the Support Team Assessment Schedule, performance status, communication levels on the Communication Capacity Scale, presence or absence of delirium, opioid consumption, and adverse effects before and one week after the procedure on the basis of retrospective chart review. A total of 162 interventions in 136 patients were obtained, comprising 3.8% of all patients receiving specialized palliative care services during the study period. Common procedures were epidural nerve block with local anesthetic and/or opioids (n = 84), neurolytic sympathetic plexus block (n = 24), and intrathecal nerve block with phenol (n = 21). There were significant differences in the frequency of neural blockade between palliative care units and palliative care teams (3.1% vs. 4.6%, respectively, P = 0.018), and between institutions whose leading physicians are anesthesiologists or have other specialties (4.8% vs. 1.5%, respectively, P < 0.001). Pain intensity measured on the Support Team Assessment Schedule (2.9 +/- 0.8 to 1.7 +/- 0.9, P < 0.001), performance status (2.7 +/- 1.0 to 2.4 +/- 1.0, P < 0.001), and opioid consumption (248 +/- 348 to 186 +/- 288 mg morphine equivalent/day, P < 0.001) were significantly improved after interventions. There was a tendency toward improvement in the communication level measured on the Communication Capacity Scale. There was no significant improvement in the prevalence of delirium, but six patients (32%) recovered from delirium after interventions. Adverse effects occurred in 9.2%, but all were predictable or transient. No fatal complications were reported. Pain intensity was significantly more improved in patients who survived 28 days or longer than others (P = 0.002). There were no significant correlations of changes in pain intensity with the performance status or previous opioid consumption. In conclusion, neural blockade was performed in 3.8% of cancer patients who received specialized palliative care services in Japan. Neural blockade could contribute to the improvement of pain intensity, performance service status, and opioid consumption without unpredictable serious side effects.

The effects of nicardipine given after 10-minutes complete global cerebral ischemia on neurologic recovery in dogs.

The effect of nicardipine (NC) on neurologic recovery from ischemic insult after 10-minutes complete global cerebral ischemia was evaluated in dogs by examination of neurologic recovery score (NRS: complete recovery=100, death = 0). Ischemia was achieved by occlusion of ascending aorta, and NC, 10 I1g·kg-1 in bolus followed by infusion of 0.33μg·kg−1·min−1 for 2 hours, was administered immediately after re-establishment of circulation. The mortality at 7th day was 2/9 in the control (C) and 1/9 in the NC group (ns). NRS on 2nd day was 52.3 ±6.8 in the C and 70.6±6.5 in the NC (P<0.05), but that on 7th day did not differ between the two groups. The numbers of dogs recovered to over 80 in NRS on the 2nd day was 1/9 in the C and 5/9 in the NC (P<0.05), but that on the 7th day increased to 3/9 in the C and remained at 5/9 in the NC (ns). These results suggest that NC accelerates the early neurologic recovery from ischemic damage, but influences little the final outcome.

A prospective, multicenter cohort study to validate a simple performance status-based survival prediction system for oncologists.

Survival prediction systems such as the Palliative Prognostic Index (PPI), which includes the Palliative Performance Scale (PPS), are used to estimate survival for terminally ill patients. Oncologists are, however, less familiar with the PPS in comparison with the Eastern Cooperative Oncology Group (ECOG) performance status (PS). This study was designed to validate a simple survival prediction system for oncologists, the Performance Status–Based Palliative Prognostic Index (PS‐PPI), which is a modified form of the PPI based on the ECOG PS.

The effects of calcium antagonists on EEG, evoked potentials and neurologic recovery after complete global brain ischemia for 15 minutes in dogs

The effects of three calcium antagonists on the recovery from neurologic damages after complete global brain ischemia were examined by evaluating the change of a electroencephalogram (EEG), evoked potentials (EP) and a neurologic recovery score (NRS) in dogs. Fifteen minutes global brain ischemia was achieved by occluding the ascending aorta and the caval veins. Nicardipine (NC), flunarizine (FL) and diltiazem (DL) were administered with continuous infusions for three days after the ischemia. The EEG-EP scores (O:no response-6:normal) 3 hr after the ischemia were 1.4±0.4 (mean ±SE) in the control, 2.2±0.3 in the NC, 2.2±0.4 in the FL and 2.1±0.2 in the DL. There were no significant differences between the 4 groups. The survival rates on the 7th day after the ischemia were 67% (6/9) in the control, 78% (7/9) in the NC, 56% (5/9) in the FL and 89% (8/9) in the DL. No significant differences were presented between the 4 groups. The NRSs (0:death − 100:normal) on the 7th day were 40.3±7.3 in the control, 59.0±8.5 in the NC, 63.2±9.7 in the FL and 55.7±3.3 in the DL. Each treated group showed a tendency to have a higher NRS than that in the untreated control group. The NRS in all dogs treated by the Ca++ antagonists on the 7th day was 58.7±4.1, which was significantly higher than that in the control group (P<0.05). We conclude that the continupus administration of calcium antagonists for three days after the global brain ischemia would be beneficial for the neurologic recovery.

Flecainide is effective against premature supraventricular and ventricular contractions during general anesthesia

The effect of intravenously administered flecainide on premature supraventricular (PSCs) and ventricular contractions (PVCs) which developed under general anesthesia was evaluated. Flecainide was infused intravenously at a rate of 0.2 mg/kg/min until the efficacy of this drug appeared or for 10 min; thus, the maximum dose was determined to be 2 mg/kg. Flecainide was administered to 10 patients who experienced more than 5 supraventricular and/or ventricular contractions/min for a period of more than 5 min (PVCs, 4 patients; PSCs, 6 patients). PVCs in 4/4 cases and PSCs in 5/6 cases disappeared following administration of flecainide. The average dose of flecainide was 1.08±0.17 mg/kg (SE). This dose of flecainide did not affect the heart rate and QRS interval, but caused a transient decrease in systolic blood pressure from 127±6 mmHg (SE) to 114±6 mmHg, a 14% increase in the PQ interval, and a 6.3% increase in the QT interval. These results suggest that flecainide is a promising drug for the treatment of PSCs and PVCs which develop during general anesthesia. Transient hypotension and cardiac conduction disturbances immediately after injection may occur when flecainide is used intravenously.

Elevation of the extracellular glutamate concentration in the hippocampus after total cerebral ischemia related to the deterioration of the recovery in EEG and evoked potentials in dogs.

The concentrations of extracellular glutamate (Glu), aspartate (Asp) and glycine (Gly) were measured by microdialysis method in the cortex and hippocampus before, during and after 15 min of total cerebral ischemia in dogs. The correlations between the concentrations of amino acids and the changes in EEG and evoked potentials (EP) after ischemia were evaluated. Total cerebral ischemia was achieved by occluding the ascending aorta and the caval veins. The concentrations of Glu in the hippocampus significantly increased from 1.73±0.59 (mean±SEM) nmol·ml−1 at pre-ischemia to 5.46±1.34 (P<0.05) during ischemia and 14.37±3.70 (P<0.01) 0–15 min after ischemia, and returned to the pre-ischemic level 30 min after ischemia. The concentration of hippocampal Glu 0–15 min after ischemia had significant negative correlations with the EEG-EP scores (0=serious deterioration of electrical function and 6=normal electrical function) 30 min, 3 hr and 5hr after ischemia (r=−0.69,P<0.05: r=−0.67,P<0.05: r=−0.70,P<0.05, respectively). The increase of the extracellular Glu concentration in the hippocampus immediately after ischemia may aggravate the neurological outcome after total cerebral ischemia.