Clinical study of blood purification therapy in critical care in Japan: results from the survey research of the Japan Society for Blood Purification in Critical Care in 2013.

To clarify the clinical status of blood purification therapy (BPT) in critical care in Japan, we conducted a cohort study using data from a nationwide registry of the Japan Society for Blood Purification in Critical Care in 2013. We enrolled 2227 patients treated with BPT (female, 39.1%; mean age, 65.5 ± 12.1 years) in the intensive care units of 43 facilities. Patient characteristics, modes of BPT, and survival rate for each disease were investigated. In total, BPT was performed 3053 times. Continuous renal replacement therapy (CRRT) (57.9%) was the most common mode of BPT, followed by intermittent renal replacement therapy (20.2%) and direct hemoperfusion with the polymyxin B-immobilized fiber column (PMX-DHP) (11.5%). Nafamostat mesilate (84.9%) was most frequently used as the anticoagulant. The 28-day survival rate was 56.8% in all patients. The most common mode for acute kidney injury (AKI) and multiple organ failure was CRRT, while PMX-DHP and CRRT were most common for sepsis. There was no significant difference in survival rates among AKI stages 1-3. Survival rate (38.3%) was significantly lower in patients with acute lung injury (ALI) than in those with multiple organ failure (41.8%) and those with sepsis (46.6%). Multivariate regression analysis revealed that the APACHE II score and the presence of acute ALI and acute hepatic failure were significantly associated with death. This large-scale cohort study showed the clinical status of BPT in Japan. Further investigations are required to clarify the efficacy of BPT for critically ill patients.

Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report.

BACKGROUND/AIM: We investigated the clinical efficacy of continuous hemodiafiltration (CHDF) with AN69ST hemofilter (AN69ST-CHDF) in patients with septic shock. MATERIALS AND METHODS: A prospective, multicenter, single-arm study was conducted. Patients with sepsis and shock defined by hyperlactemia were enrolled. The patients were treated with CHDF and in accordance with the Surviving Sepsis Campaign guidelines (SSCG). RESULTS: Thirty-four patients were enrolled. On ICU admission, the mean blood IL-6 level was 44,800 ± 77,700 pg/ml, and the mean blood lactate level was 69.0 ± 49.4 mg/dl. Both the mean blood IL-6 and lactate levels had significantly decreased to normal ranges after 72 h of AN69ST-CHDF. Though the mean APACHE II score was 32.7 ± 9.8, 28-day survival was 73.5%. CONCLUSION: The current study suggested that adding AN69ST-CHDF to the treatments outlined in the SSCG might lead to good outcomes for patients with septic shock, probably via the removal of cytokines from the bloodstream.

Urinary neutrophil gelatinase-associated lipocalin and plasma IL-6 in discontinuation of continuous venovenous hemodiafiltration for severe acute kidney injury: a multicenter prospective observational study.

BACKGROUND: Patients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF. METHODS: This prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence. RESULTS: A total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p < 0.01), whereas no significant difference was observed in plasma IL-6 between the groups. Temporal elevations of urinary NGAL levels during the first 48 h since CVVHDF initiation were observed in CVVHDF nonsurvivors and those who failed in CVVHDF discontinuation. CONCLUSIONS: Urinary NGAL at CVVHDF initiation and discontinuation was associated with mortality and RRT dependence, respectively. The serial changes of urinary NGAL might also help predict the prognosis of patients with AKI on CVVHDF.

Continuous hemodiafiltration with a cytokine-adsorbing hemofilter for sepsis.

Since the introduction of the new pathophysiological concept of pathogen-associated molecular patterns (PAMPS) and alarmins, endotoxin has been recognized as only one of the PAMPS. It is widely accepted that hypercytokinemia plays a pivotal role in the pathophysiology of sepsis. Many kinds of blood purification modalities have been proposed as a therapeutic tool against sepsis, including high-volume continuous hemofiltration whose efficacy has recently been questioned. We report that continuous hemodiafiltration (CHDF) with a cytokine-adsorbing hemofilter (CAH), such as polymethyl methacrylate hemofilter and AN69ST hemofilter (CAH-CHDF), can remove many kinds of cytokines and has been very effective in the treatment of severe sepsis and septic shock. Based on the understanding of the recent pathophysiology, we suggest that CAH-CHDF is an alternate therapy to direct hemoperfusion with endotoxin-adsorbing column in the treatment of sepsis.

Results of the 2018 Japan Society for Blood Purification in Critical Care survey: current status and outcomes.

Background: The Japan Society for Blood Purification in Critical Care (JSBPCC) has reported survey results on blood purification therapy (BPT) for critically ill patients in 2005, 2009, and 2013. To clarify the current clinical status, including details of the modes used, treated diseases, and survival rate, we conducted this cohort study using data from the nationwide JSBPCC registry in 2018. Methods: We analyzed data of 2371 patients who underwent BPT in the intensive care units of 43 facilities to investigate patient characteristics, disease severity, modes of BPTs, including the dose of continuous renal replacement therapy (CRRT) and hemofilters, treated diseases, and the survival rate for each disease. Disease severity was assessed using Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores. Results: BPT was performed 2867 times in the 2371 patients. Mean APACHE II and SOFA scores were 23.5 ± 9.4 and 10.0 ± 4.4, respectively. The most frequently used mode of BPT was CRRT (67.4%), followed by intermittent renal replacement therapy (19.1%) and direct hemoperfusion with the polymyxin B-immobilized fiber column (7.3%). The most commonly used anticoagulant was nafamostat mesilate (78.6%). Among all patients, the 28-day survival rate was 61.7%. CRRT was the most commonly used mode for many diseases, including acute kidney injury (AKI), multiple organ failure (MOF), and sepsis. The survival rate decreased according to the severity of AKI (P = 0.001). The survival rate was significantly lower in patients with multiple organ failure (MOF) (34.6%) compared with acute lung injury (ALI) (48.0%) and sepsis (58.0%). Multivariate logistic regression analysis revealed that sepsis, ALI, acute liver failure, cardiovascular hypotension, central nervous system disorders, and higher APACHE II scores were significant predictors of higher 28-day mortality. Conclusion: This large-scale cohort study revealed the current status of BPT in Japan. It was found that CRRT was the most frequently used mode for critically ill patients in Japan and that 28-day survival was lower in those with MOF or sepsis. Further investigations are required to clarify the efficacy of BPT for critically ill patients.Trial Registration : UMIN000027678. Supplementary Information: The online version contains supplementary material available at 10.1186/s41100-022-00445-0.

Efficacy of high-flow dialysate continuous hemodiafiltration in the treatment of fulminant hepatic failure.

We compared the clinical efficacy of high-flow dialysate continuous hemodiafiltration (HFCHDF) performed as artificial liver support (ALS) in fulminant hepatic failure (FHF) with those of conventional ALS techniques. Ninety patients were divided into non-HFCHDF and HFCHDF groups. Rate of recovery from coma was significantly higher in the HFCHDF group (70.2%) than in the non-HFCHDF group (44.2%) (p<0.01). The excellent recovery rate from coma achieved in patients with FHF by HFCHDF may be due to its enhanced capacity for liver support enabling efficient removal of substances causing hepatic coma from blood. HFCHDF should thus be useful for ALS.

Oral care reduces incidence of ventilator-associated pneumonia in ICU populations.

OBJECTIVE: To examine whether oral care contributes to preventing ventilator-associated pneumonia (VAP) in ICU patients. DESIGN: Nonrandomized trial with historical controls. SETTING: A medical-surgical ICU in a university hospital. PATIENTS: 1,666 mechanically ventilated patients admitted to the ICU. INTERVENTION: Oral care was provided to 1,252 patients who were admitted to the ICU during period between January 1997 and December 2002 (oral care group), while 414 patients who were admitted to the ICU during period between January 1995 and December 1996 and who did not receive oral care served as historical controls (non-oral care group). MEASUREMENTS AND RESULTS: Incidence of VAP(episodes of pneumonia per 1000 ventilator days) in the oral care group was significantly lower than that in the non-oral care group (3.9 vs 10.4). The relative risk of VAP in the oral care group compared to that in the non-oral care group was 0.37, with an attributable risk of -3.96%. Furthermore, length of stay in ICU before onset of VAP was greater in the oral care than in the non-oral care group (8.5+/-4.6 vs 6.3+/-7.5 days). However, no significant difference was observed in either duration of mechanical ventilation or length of stay between the groups (5.9+/-10.8 vs 6.0+/-8.8 days and 7.5+/-11.5 vs 7.2+/-9.5 days, respectively). Pseudomonoas aeruginosa was the most frequently detected bacteria in both groups. Number of potentially pathogenic bacteria in oral cavity was significantly reduced by single oral care procedure. CONCLUSION: Oral care decreased the incidence of VAP in ICU patients. DESCRIPTOR: Pulmonary nosocomial infection.

Blood purification for hypercytokinemia.

Blood purification has been steadily improved in the field of critical care, supported by advances in related biomedical technologies as well as efforts to develop better operating procedures. As it has become clear that hypercytokinemia plays a key role in the pathophysiology of critical pathological conditions, use of various blood purification techniques to control hypercytokinemia has been investigated. Answers to questions concerning the optimal cytokine-removing device (dialyzer/hemofilter/adsorber) as well as operating procedures and conditions of such devices in particular clinical conditions have been obtained in the course of such investigations. The recent success in real-time monitoring of cytokine levels in clinical practice to assess the extent of cytokine network activation may improve the precision and efficacy of blood purification in the treatment of hypercytokinemia. In addition, the recently documented effects of genetic factors on hypercytokinemia suggest that the introduction of tailor-made medicine considering the differences in genetic background among individual patients may improve the efficacy of blood purification as a countermeasure to hypercytokinemia.

Management of intra-abdominal hypertension in patients with severe acute pancreatitis with continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter.

To evaluate, with a prospective observational study, whether continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter (PMMA-CHDF) is effective for prevention and treatment of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on patients with severe acute pancreatitis (SAP). The study was carried out in the general intensive care unit (ICU) of a university hospital. Seventeen consecutive patients with SAP were treated in the intensive care unit and underwent PMMA-CHDF whether or not they had renal failure. Blood level of interleukin (IL)-6, as an indicator of cytokine network activation, and intra-abdominal pressure (IAP) were measured daily to investigate their time-course of changes and the correlation between the two. The blood level of IL-6 was high at 1350+/-1540 pg/mL on admission to the ICU. However, it significantly decreased to 679+/-594 pg/mL 24 h after initiation of PMMA-CHDF (P<0.05), and thereafter decreased rapidly. Mean intra-abdominal pressure (IAP) on admission was high, at 14.6+/-5.3 mm Hg, with an IAP of 20 mm Hg or over in 2 of 17 patients, showing that they had already developed IAH. The IAP was significantly lower (P<0.05) 24 h after initiation of PMMA-CHDF, and subsequently decreased. There was a significant positive correlation between blood level of IL-6 and IAP, suggesting that PMMA-CHDF improved vascular permeability through elimination of cytokines, and that it thereby decreased interstitial edema to lower IAP. Sixteen of the 17 patients were discharged from the hospital in remission from SAP without development of complications. Continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter appears to be effective for prevention and treatment of IAH in patients with SAP through the removal of causative cytokines of hyperpermeability.

Continuous hemodiafiltration in pediatric critical care patients.

Continuous hemodiafiltration (CHDF) is an essential procedure in critical care. However, application of this therapy to pediatric patients is associated with several problems derived from their smaller body size and weight compared with adults. We have successfully conducted CHDF in pediatric patients including newborns by taking such problems into consideration and carefully coping with them. The present study consisted of 60 pediatric patients treated with CHDF. Clinical efficacy and safety of CHDF in pediatric patients were assessed in these patients by reviewing patient clinical records. The 60 patients treated with CHDF included 27 males and 33 females. Their body weight ranged from 700 g to 53.0 kg. The mean CHDF duration was 6.80 +/- 6.94 days. Blood access was provided in a veno-venous mode in 42 patients, and an arterio-venous mode in 18 patients. Of the 60 pediatric patients receiving CHDF, 31 patients survived without serious complications, achieving a survival rate of 51.7%. Successful CHDF in pediatric patients was achieved by careful and exact execution of the following countermeasures to overcome problems specific to application of this therapy to pediatric patients: minimization of the priming volume; use of colloid solutions or whole blood as priming solution; maintaining secure blood access; selection of an appropriate anticoagulant; temperature control of both the patient's body and components of the hemofiltration circuit. In pediatric critical care, CHDF is safely applicable to the critically ill and expected to produce a wide spectrum of clinical efficacy just as in adults.

The change in renal replacement therapy on acute renal failure in a general intensive care unit in a university hospital and its clinical efficacy: a Japanese experience.

The aim of our study was to examine renal replacement therapies (RRT) that have been used for acute renal failure (ARF) in our intensive care unit (ICU) patients and to compare their outcomes. Sixteen patients who underwent intermittent hemodialysis (IHD), 14 patients who underwent continuous hemofiltration (CHF) in combination with IHD (CHF + IHD), and 38 patients who underwent continuous hemodiafiltration (CHDF) were evaluated. Regarding the effects of blood purification on hemodynamics and renal function, the percentage increase in blood pressure and percent rapid increase in urinary output were the greatest in the CHDF group. The hourly urinary output after the start of initial blood purification increased only in the CHDF group. The survival rate was significantly higher in the CHDF group. These results suggest that CHDF should be the first-line therapy for patients with ARF and that we are moving in the right direction regarding the application of RRT to treat ARF in ICU patients.

[Endotoxin removal in septic shock].

Endotoxin adsorption therapy with a column containing polymyxin B-immobilized fiber (PMX-DHP) has been widely applied in the treatment of endotoxin-induced septic shock in Japan. Recently, the indications for PMX-DHP have been expanded as it has become clear that anandamide can be removed from the bloodstream with PMX-DHP. On the other hand, continuous hemodiafiltration with a polymethyl methacrylate (PMMA) membrane hemofilter(PMMA-CHDF) is performed to remove various humoral mediators from the bloodstream in the ICU in many hospitals because it has been accepted that those humoral mediators play a more important role in the pathogenesis of septic shock than endotoxins. According to our own results, there were no differences in the endotoxin removal rate, anandamide removal rate, and survival rate with or without PMX-DHP during PMMA-CHDF in the treatment of patients with septic shock. These results indicate that there is no need to perform PMX-DHP for septic shock as long as PMMA-CHDF is performed, and that the indications for PMX-DHP should be circumspectly investigated again.

[Humoral mediators in the pathophysiology of organ dysfunction in sepsis].

It is recognized that various humoral mediators, especially inflammatory cytokines such as tumor necrosis-factor-alpha and interleukin (IL)-1 beta, play a key role in the pathophysiology of septic shock and organ dysfunction following severe infection. We have recently begun to employ a rapid measurement system that allows us to measure blood IL-6 levels within 30 min using a chemiluminescent enzyme immunoassay. IL-6 blood levels reflect well the activation of the cytokine cascade and correlated well with the severity of patient's, condition. The ratio of simultaneously measured IL-6 blood levels in peripheral and pulmonary arteries is useful to identify the site responsible for cytokine production. Early initiation of PMMA-CHDF as a cytokine modulator of septic shock results in improved recovery from shock and in improved outcome. Genetic analysis of cytokine-related genes revealed a high frequency of a specific genotype in patients who have extremely high IL-6 blood levels. Screening of patients at high risk of hypercytokinemia with the specific genotype would enable appropriate treatments and contribute to future tailor-made medicine.

[Indications for and clinical efficacy of continuous hemodiafiltration (CHDF) for severe acute pancreatitis].

It has been claimed humoral mediator network including pro-inflammatory cytokines plays a pivotal role in the pathophysiology of SAP. On the other hands, we have reported CHDF using polymethyl methacrylate (PMMA) membrane hemofilter could remove cytokines in blood of a patient continuously and effectively. Therefore, we applied CHDF to patients with SAP. CHDF was performed using a PMMA-hemofilter for removal of causative cytokines regardless of renal function 24 hours a day without interruption until IL-6 blood level became below 400 pg/ml. Selective digestive decontamination (SDD) was also given for prevention of bacterial translocation. Forty-two out of 45 patients (93%) receiving both CHDF and SDD survived. We conclude critical care with PMMA-CHDF and SDD is an effective treatment for SAP.

Special considerations in continuous hemodiafiltration with critically ill pediatric patients.

Continuous hemodiafiltration (CHDF) has become an essential procedure in critical care. However, effective application of this modality to pediatric patients is associated with several problems derived from their smaller body size and weight compared with adults. We have successfully conducted CHDF in pediatric patients, even newborns, by taking such problems into consideration and navigating around them. Successful CHDF in pediatric patients was achieved by careful and exact execution of the following countermeasures to overcome pediatric-specific problems: minimization of the priming volume; use of colloid solutions or whole blood as priming solution; maintaining secure vascular access; selection of an appropriate anticoagulant; temperature control of both the patient's body and components of the hemofiltration circuit. In pediatric critical care, CHDF is safe and expected to demonstrate clinical efficacy across a wide spectrum of clinical problems, just as in adults.

Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis.

This study was undertaken to investigate whether sequential measurement of blood interleukin (IL)-6 levels using chemiluminescent enzyme immunoassay (CLEIA) would be useful for the management of patients with systemic inflammatory response syndrome (SIRS)/sepsis. Forty consecutive patients with SIRS/sepsis admitted to ICU were involved in the study. Blood IL-6 level was measured everyday throughout their ICU stay at the clinical laboratory by CLEIA method. The platelet count and the sequential organ failure assessment (SOFA) score were measured consecutively. The blood IL-6 levels were elevated in SIRS/sepsis patients and were extremely high in patients with septic shock. There was no significant difference in the blood IL-6 level on admission between survivors (n=27) and non-survivors (n=13). However, the mean blood IL-6 level during ICU stay was significantly higher in the non-survivors (p<0.05). There were significant correlation between the peak IL-6 blood level and the lowest platelet count, and between the peak IL-6 blood level and the maximum SOFA score, respectively. The platelet count became lowest 2.0+/-2.0 days later on average, and the SOFA score became maximal 2.5+/-1.4 days later on average following the day when IL-6 reached its peak value. Sequential measurement of blood IL-6 levels by CLEIA is useful in evaluating the severity and in predicting the outcome of the patients with SIRS/sepsis.

Cytokine-related genotypic differences in peak interleukin-6 blood levels of patients with SIRS and septic complications.

BACKGROUND: The aim of the present study was to investigate whether tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6-related genotypic differences affect IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS) in an intensive care unit (ICU). METHODS: Seven polymorphisms of TNF, IL-1, and IL-6-related polymorphisms were studied with an allele-specific polymerase chain reaction. One hundred and thirteen patients diagnosed with SIRS whose sequential organ failure assessment scores were > or =5 at the time when their daily measured IL-6 blood level peaked during the ICU stay (IL-6 max) were examined. IL-6 max, survival, and septic complications were compared between carriers and non-carriers of less frequent alleles, indicated as allele*2, in each polymorphism. RESULTS: In single nucleotide polymorphism (SNP) at position -238 site of TNF-alpha (TNF-alpha-238*G/A), IL-6-596*G/A, and IL-6-174*C/T, allele*2 frequencies were much lower in the Japanese than in the Caucasian population. IL-6 max was significantly higher in allele*2 carriers of IL-1beta-511*C/T. Associations were found between susceptibility to septic shock and allele*2 carriage for both IL-1beta-511*C/T and TNF-alpha-308*G/A, and also between poor prognosis and allele*2 carriage in both IL-1 receptor antagonist second intron various number of tandem repeats polymorphism (IL-1raRN*1-5) and TNF-alpha-308*G/A. IL-1beta-511*C/T and IL-1raRN*1-5 were in linkage disequilibrium in this study population. CONCLUSIONS: Carriers of less frequent alleles in IL-1-related polymorphisms appear to have significant vulnerability to production of excessive IL-6 blood levels and to deterioration in septic shock.