The therapeutic effect of high-volume hemofiltration on sepsis: a systematic review and meta-analysis

Introduction

Worldwide, 31.5 million cases of sepsis occur each year, resulting in 5.3 million deaths (1). Increasing incidence of sepsis has been observed in recent years. Although the treatment of sepsis has progressed, including early fluid resuscitation, antimicrobial therapy and mechanical ventilation, sepsis remains the leading cause of death in the intensive care unit (ICU) (1,2). Continuous renal replacement therapy (CRRT) which can precisely control fluid balance and remove metabolic waste has been widely used in the treatment of sepsis (3). Continuous veno-venous hemofiltration (CVVH) is one of the most commonly used modes. Convection is the main way to remove solutes in CVVH, it depends on the hydrostatic pressure on both sides of the membrane and accompanied by ultrafiltration (4). Whether high ultrafiltrate volume in CVVH is beneficial for sepsis survival than conventional volume hemofiltration (CVHF) is unclear. In addition, the definition of high volume during CVVH treatment remains controversial. In 2001, Ronco et al. proposed an ultrafiltrate volume of 20–35 mL/kg/h for traditional doses, >42.8 mL/kg/h as large doses (5); Bellomo et al. proposed to define ultrafiltrate volume >60 L/d as high-volume hemofiltration (HVHF) (6), Honore et al. recommended an ultrafiltrate volume >50 mL/kg/h as HVHF (7). In 2002, Acute Dialysis Quality Initiative (ADQI) defined ultrafiltrate volume >35 mL/kg/h as HVHF (8). In 2012, Joannes-Boyau et al. believed that HVHF meant continuous ultrafiltrate volume of >50 mL/kg/h for 24 h (9). But most articles in this field use 35 mL/kg/h as the definition of high volume in CVVH therapy. We intend to evaluate the effect of HVHF in sepsis by systematic review and meta-analysis.

Methods

Study search strategy

Investigators (F Yin, F Zhang) systematically and independently searched the Medline, Embase, Cochrane library databases to June 21 2019. The literature search included the keywords and MeSH terms “sepsis” “continuous blood purification” “continuous renal replacement therapy” “continuous veno-venous hemodiafiltration” and “continuous veno-venous hemofiltration” with no language restrictions.

Study selection

Investigators (F Yin, F Zhang) independently determined study eligibility by reviewing and retrieving the literatures by titles or abstracts, and subsequently the full texts. Different opinions on reviewing was resolved through consensus with an arbitrator (S Liu). The studies were included in this review if they met the following criteria: participants in studies are more than 18 years; study type is randomized controlled trail (RCT); a ultrafiltrate volume in interval group was greater than 35 mL/kg/h; the outcomes contained mortality; the sepsis meets the diagnostic criteria in the Society of Critical Care Medicine/European Society of Intensive Care Med/American College of Chest Physicians/American Thoracic Society/Surgical Infection Society (SCCM/ESICM/ACCP/ATS/SIS) (10) or the Third International Consensus Definitions for Sepsis and Septic Shock (11). Studies were excluded if non-sepsis patients included in the study; treatment type is not CVVH, such as: continuous veno-venous hemodiafiltration (CVVHDF); duplicate articles described in the same study.

Data extraction and quality assessment

Two reviewers (F Yin, F Zhang) independently extracted data elements from each trial, including patients baseline characteristics, study characteristics and CRRT intervention, mortality related endpoints and other endpoints. We contacted the author of the paper to confirm unclear data. We used RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Demark) to assess risk of bias and quality of each included literatures. Through the authors judgement, we clarified the risk of bias as “low” “high” or “unclear”. Publication bias was detected by visual symmetry of funnel plots, with asymmetry suggesting possible publication bias. This study was approved by the ethical committee of Shanghai Children’s Medical Center. The approval number is SCMCIRB-W2020001.

Statistical analysis

We enrolled and analyzed data using RevMan 5.3 software. We used risk ratio (RR) with 95% confidence interval (CI) for the statistical analysis of dichotomous data, summary statistic in this review was performed using a forest plot. Heterogeneity was assessed by the P value and the I-square statistic (I²) in the pooled analyses, which represents the percentage of total variation across studies (12). If the P value was less than 0.1 or the I²-value was greater than 50%, the summary estimate was analyzed in a random-effects model. Otherwise, a fixed-effects model was applied.

Results

Study characteristics and quality assessment

We found 1,728 relevant literatures in the initial search from Medline and Embase, of which 225 were excluded because of duplication. Of the remaining 1,503 studies, 1,402 were excluded after reviewing the titles and abstracts. After reviewed the full texts, 86 studies were excluded in accordance to the eligibility criteria. Eligibility of the remaining 15 studies was assessed. Among these, 5 studies that included 241 patients published between 2006 and 2016 were included for meta-analysis for efficacy assessment of HVHF in septic patients. Literature screening strategies was showed in a flowchart (Figure 1). The included studies were geographically diverse: one study was conducted in America, one in Australia, two in Europe, and the remaining one in Asia. We used the mortality related endpoints as an indicator of the efficacy of HVHF. Characteristics of the enrolled studies such as trail design, type of anticoagulation, ultrafiltrate volume and ultrafiltrate volume were presented in Table 1. Patient baseline characteristics were shown in Table 2.

Figure 1 Study selection flow diagram.

Table 1 Study characteristics and CRRT intervention
Full table

Table 2 Patient baseline characteristics
Full table

Our meta-analysis was concentrating on the effect of HVHF in sepsis. Fifteen clinical trials were identified, only five of them qualifying for quantitative synthesis. Piccinni et al. in 2006 (13) and Cui et al. in 2015 (14) were excluded because there were observation studies; Ronco et al. in 2000 (15), Vesconi et al. in 2009 (16), Palevsky et al. in 2008 (17) were not included because the participants enrolled were not all sepsis patients. The record from Honore et al. in 2000 (7), Joannes-Boyau et al. in 2004 (18), Cornejo et al. in 2006 (19) had to be excluded because there were single arm trails. Due to conducting blood purification without HVHF, Mayumi et al. in 2016 (20) were excluded after reviewing. Zhang et al. in 2012 (21) compared the impact of HVHF (50 mL/kg/h) and extra HVHF (85 mL/kg/h) on sepsis, which didn’t meet our inclusion criteria.

We have evaluated the risk of bias and quality of each literatures. Figure 2 showed the results of enrolled literature quality evaluation. In the random sequence generation, all studies were at low risk of selection bias; in the allocation concealment, three studies had low risk of bias, one study (22) (Ghani et al. in 2006) had unclear risk of bias due to insufficient information available, another (23) (Boussekey et al. in 2008) had high risk of bias because of the randomized group for the last participant in each block was known in advance; in blinding of participants and personnel, four studies were at low risk, one study (24) (Chung et al. in 2017) had high risk of bias because of open-label trials; in blinding of outcome assessment, one study were at low risk, while remaining study (22-25) had unclear risk due to insufficient information available; in incomplete outcome data, two studies had low risk of bias, three studies (9,22,23) had unclear risk of bias because relevant data was not available from the original text and trial registration website. Only one study (23) had unclear risk of reporting bias. Publication bias was detected by visual symmetry of funnel plots. In the evaluation of mortality related endpoints, a total of 3 studies were included. Asymmetry suggesting possible publication bias, the funnel plot (Figure 3) showed no obvious asymmetrically, we thought there was no potential publication bias.

Figure 2 Results of literature quality assessment.

Figure 3 The funnel plot of the publication bias analysis.

Mortality related endpoints

Joannes-Boyau et al. (9), Boussekey et al. (23) and Chung et al. (24) reported 28-day mortality, the pooled risk ratio (RR) for the three trails of 28-day mortality was 0.96 (0.67, 1.38). Figure 4 represented the pooled results of 28-day mortality. Due to small sample size, it was difficult to perform a summary analysis of all mortality related endpoints. Joannes-Boyau et al. (9) also reported 60-day mortality (49% in CVHF, 50% in HVHF) and 90-day mortality (50.7% in CVHF, 56% in HVHF). Ghani et al. (22) reported a mortality of 76% (25/33), but the type of mortality was unknown. Cole et al. (25) used a cross-over design and reported hospital mortality of 54.5% (5/11). All mortality related endpoints of enrolled studies were presented in Table 3.

Figure 4 Forest plot of comparison in relative risk of mortality.

Table 3 Mortality related endpoints
Full table

Other endpoints

Except for mortality related endpoints, enrolled studies also reported other endpoints including length of hospital/ICU stay, organ function assessment, hemodynamic changes and cytokine clearance. The incomplete data of the enrolled studies resulted in difficulty in pooling estimates for these endpoints. All these endpoints were shown in Table 4.

Table 4 Other endpoints
Full table

Length of stay

Three studies investigated the length of stay. Among then, Boussekey et al. (23) and Chung et al. (24) recorded the length of ICU stay. Joannes-Boyau et al. (9) reported the ICU-free day. Both groups in the three studies showed no significant difference in the length of stay.

Organ function evaluation

Four studies evaluated the organ function through critical illness scores. Ghani et al. (22) measured Sequential Organ Failure Assessment (SOFA) scores at day 0, 1 and 7. SOFA scores at baseline were similar between the two treatment groups. Both groups showed a significant reduction in the SOFA scores at day 7 compared to baseline (HVHF, P=0.048; CVHF, P=0.006). Chung et al. (24) found MODs scores decreased significantly in the HVHF group when compared to the day of treatment initiation (P=0.02). Both Ghani et al. (22) and Chung et al. (24) did not report the results of comparation between groups (CVHF and HVHF).

SOFA scores and simplified acute physiology score (SAPS) II scores at days 4 and 28 in the study of Joannes-Boyau et al. (9) showed no significant difference between two groups. This goes along with the finding of Boussekey et al. (23), who found no significant difference of logistic organ dysfunction (LOD) scores between two groups.

Effect on hemodynamics

All studies evaluated the effect on hemodynamics changes after intervention. Except for studies of Boussekey et al. (23), the remaining studies did not reported the hemodynamic changes between groups. Boussekey et al. (23) could not detect a difference of mean arterial pressure (MAP) in both groups. Only Chung et al. (24) reported a significant reduction of vasopressor dependency index (VDI) in HVHF group compared to baseline. Other studies failed to find differences on hemodynamic metrics including MAP in both groups compared to baseline.

Cytokine clearance

Among the included studies, 3 studies measured serum cytokine levels. The results of comparation between groups (CVHF and HVHF) were showed below. Ghani et al. (22) could not detect a difference of interleukin (IL)-6 level between two groups, while the HVHF group demonstrated a reduction of the serum IL-1-ra levels compared with an increase in the CVHF group (3 h, P=0.007; 6 h, P=0.036). In the study of Chung et al. (24), the levels of IL-6, IL-8, IL-10, IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured over the intervention period, no cytokines showed difference at each time point between the two groups. This goes along with the finding of Cole et al. (25), who found no significant reduction of complement C3a, C5a, IL-10, IL-8, TNF-α levels between two groups. In contrast, Chung et al. (24) could not detect any reduction in IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α in both groups at all time points compared to baseline.

The results of comparation within groups (CVHF and HVHF) were showed below. Cole et al. (25) discovered significant lower level of IL-6 at 6 hours HVHF group compared to baseline. This goes along with the finding of Ghani et al. (22), who found a significant decrease of IL-8, TNF-α levels (P<0.01) only in patients treated with HVHF. But Chung et al. (24) found there were no significant reduction in IL-6, IL-8, IL-10, IL-12, IFN-γ levels at all time points in both groups compared to baseline.

Respiratory function

Only Joannes-Boyau et al. (9) and Boussekey et al. (23) reported metrics in respiratory function. The former evaluated partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO₂/FiO₂), the latter investigated ((PaO₂/FiO₂) and duration of mechanical ventilation. Both studies found no significant difference in respiratory function metrics.

Discussion

Sepsis, especial septic shock, remains the leading cause of death in ICU, which is associated with patients’ poor prognosis (26). 3.0 version of sepsis definition emphasizes the importance of organ dysfunction in the pathogenesis of sepsis (27). CRRT may improve organ function in patients with sepsis (28). CVVH is a commonly used mode in clinical CRRT treatment. Ultrafiltrate volume is the key to CVVH treatment in patients with sepsis. Whether high ultrafiltrate volume in CVVH is beneficial for sepsis survival remains controversial. RCTs included in this meta-analysis have different cut-off in definition of high-volume. A conventional-volume hemofiltration would be 20–25 mL/kg/h of effluent generation (28). In HVHF, the ultrafiltration volume is greater than 35 mL/kg/h (15). We continued renal replacement therapy and chose 35 mL/kg/h as thresholds to distinguish the CVHF and HVHF.

Due to different formats for reporting mortality, not all RCTs are included in the pooled analysis. The pooled RR of three trails (Joannes-Boyau et al. in 2013, Boussekey et al. in 2008, Chung et al. in 2017) failed to show improvement in 28-day mortality for patients with sepsis. No overall beneficial effects of HVHF compared to CVHF can be detected. Till now, few studies have focused on how HVHF affected the outcomes of sepsis. Only Emj et al. (29) investigate the impact of HVHF in critically ill patient in 2013 and updated the contents in 2016 (30), and got the similar results as we reported after 3 years period.

We also evaluated the effect on other endpoints of patients with HVHF intervention, including length of stay, organ function evaluation, effect on hemodynamics, cytokine clearance, respiratory function. Because of poor data consistency, we only describe the relevant endpoints.

Some trails showed that HVHF could improve organ function in patients of different ages (24,31). But in this meta-analysis, most other endpoints of enrolled studies didn’t show any significant differences between CVHF and HVHF. Some interventions show differences only when compared to baseline. Moreover, for the same endpoint, the results reported by each study differed greatly. In addition to the hemofiltration volume, the pre/post dilution ratio, and the blood flow volume can affect the trail results, thereby changing the conclusion of the meta-analysis.

There are some side-effects, such as bleeding, infection, thrombosis and thrombocytopenia. Few literatures included in this review reports HVHF related adverse events, only Joannes-Boyau 2013 described adverse events but didn’t assess whether they were directly related to HVHF. Moreover, HVHF has been widely used in the treatment of acute kidney injury (AKI) with few side effects. In addition, membrane materials for filter were constantly updated which avoid the occurrence of side effects. The safety of HVHF has been confirmed.

It is worth noting that due to lack of relevant clinical trials, pooled results come from only 5 RCTs including 241 participants (small sample size). Enrolled RCTs used different assessment methods, which lead to different participant’s condition. Additionally, the median age of participants exceeded 50 years old and lack of data on youth and children, which failed to fully reflect differences in response to treatment for patients of different ages. In addition, different maintenance time and filter of HVHF may affect the outcomes of sepsis patients. Attention should be paid to the generalization of conclusions because the limitation of the evidence. More trials with larger sample sizes and high-quality evidence are needed.

Conclusions

The available evidence on ultrafiltrate volume does not indicate effectiveness of HVHF in patients with sepsis, HVHF may be effective in improving some secondary endpoints other than mortality. But the use of HVHF is safe for sepsis patients. More larger sample sizes trails crossing all ages are needed to supplement the defects of the existing evidence.

Acknowledgments

We would like to thank Botao Ning and Shijian Liu (Content Editor) for providing advices and guidance during preparation of this systematic review.

Funding: The study was supported by the project of five innovations from Shanghai Shenkang Hospital Development Center (16CR3085B), the Key Developing Disciplines Project from Shanghai Municipal Commission of Health and Family Planning (2016ZB0104) and the Shanghai Natural Science Foundation of China (No. 19ZR1432900).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm.2020.03.48). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the ethical committee of Shanghai Children’s Medical Center (SCMCIRB-W2020001).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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