Background: Pediatric sepsis is a significant public health issue. This condition is exacerbated by rising serum creatinine and inflammatory cytokines that lead to deleterious effects upon the body. The current standard of care involves the use of continuous kidney replacement therapy to remove harmful cytokines until the body returns to homeostasis. In order to promote faster clearance and reduced stay in the ICU, high-volume hemofiltration (HVHF) has shown promise. However, there is a paucity of studies to fully elucidate its benefits. Methods: A literature search was done using PubMed/ MEDLINE and Embase. The literature was reviewed by two independent reviewers, who independently assessed the quality of randomized controlled trials by using the Cochrane risk of bias tool for RCTs and Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized controlled trials. Data were combined from studies with a similar design. Results: The primary endpoint of all-cause mortality was found to be reduced by 40% across all of the pooled studies. For secondary endpoints, significant reductions of serum creatinine were found. Additionally, duration of ICU stays and treatment course was found to be significantly shorter in HVHF patients than the current standard of care. The rate of adverse effects was analyzed, and there was no difference in the proportion of patients developing hypokalemia, hyperkalemia, hypernatremia, or hyponatremia. The proportion of patients developing hyperglycemia was higher in patients undergoing HVHF, whereas the proportions of patients developing bleeding were significantly less in patients undergoing HVHF. One study reported a total number of adverse events between the two groups which were significantly lesser in patients undergoing HVHF. Conclusion: HVHF shows promise as a modality to treat pediatric patients with sepsis. In order to confirm the benefits of this modality, future studies need significantly more patients for analysis.

Continuous kidney replacement therapy (CKRT) is a modality that utilizes convection and adsorption to remove excess inflammatory mediators in the body in order to help allow for a return to homeostasis. Additionally, it allows for the removal of toxins and excess electrolytes, restoration of acid-base equilibrium, and proper volume homeostasis. This technique is extensively applied in patients of all ages. Advantages of CKRT include water and electrolyte correction, hemodynamic stability, and improvement in kidney function [1]. This modality has also shown significant efficacy in the removal of proinflammatory and anti-inflammatory markers from the system, allowing for the return of homeostasis. High-volume hemofiltration (HVHF), a mode of CKRT, uses high-volume fluid exchange to achieve faster and more efficient removal of such markers [2, 3].

HVHF is considered to be one of the most efficacious modalities in removing systemic inflammatory markers. The convection method of HVHF provides a greater affinity gradient for both plasma and solutes across the membrane. Additionally, most inflammatory markers, mass ranges from 5 kDa to 60 kDa, can be effectively removed via a convection method as compared to the diffusion method [4, 5]. Studies have shown that increasing the ultra-filtration flow rate may play a role in increasing the absorption rate of the cytokine markers across the membrane [6‒8].

The KDIGO Clinical Practice Guidelines for acute kidney injury recommend a minimum effluent flow of 0.20–25 mL/kg per h when using CKRT. Attention to dosage delivery and monitoring is essential. In the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study [9], the patients transitioned between different modalities with different dosages; intermittent hemodialysis with a target Kt/Vurea per treatment of 1.2–1.4 either three or six times per week and continuous venovenous hemodiafiltration at 20 or 35 mL/kg/h. For the Randomized Evaluation of Normal versus Augmented level Renal Replacement Therapy (RENAL) trial [10], the patients received continuous venovenous hemodiafiltration at 25 or 40 mL/kg/h. In the Impact of High-volume Venovenous Continuous Hemofiltration in the Early Management of Septic Shock Patients with Acute Renal Failure (IVOIRE) trial, the patients received either HVHF at 70 mL/kg/h or standard-volume hemofiltration at 35 mL/kg/h for 96 h [11, 12].

Very few studies exist that investigate the optimal dosage and modality of CKRT and HVHF in the pediatric population. As such, the main purpose of this systemic review is to analyze and condense the current data evaluating the efficacy of HVHF use in pediatric patients.

Study Search Strategy

A literature search utilizing PubMed/MEDLINE and Embase. The keywords used while conducting the literature search are “hemofiltration OR hemofiltration OR hemodiafiltration” AND “high-volume.” The study was further narrowed to English language and the pediatric population (age 0–18 years).

Study Selection

The literature screening strategies applied are shown in the PICOS chart (Table 1). The included studies were all based in Asia. Mortality-related endpoints were applied as an indicator of the efficacy of HVHF. Secondary outcomes analyzed consisted of cytokine and serum creatinine clearance, adverse effects, and duration of ICU stay and are presented in Table 2.

Table 1.

PICOS table to describe the inclusion and exclusion criteria for the literature review

 PICOS table to describe the inclusion and exclusion criteria for the literature review
 PICOS table to describe the inclusion and exclusion criteria for the literature review
Table 2.

Descriptions of each study and the characteristics present for analysis

 Descriptions of each study and the characteristics present for analysis
 Descriptions of each study and the characteristics present for analysis

Data Extraction and Quality Assessment

The literature was reviewed by two independent reviewers, reviewing the titles, abstracts, and the full articles (R.C. and N.N.). Any disagreement during the data extraction was referred to a third investigator (R.R.). If the studies were eligible, data related to the safety, efficacy, and mortality were extracted. In the absence of any data, corresponding authors were contacted for the missing information. All-cause mortality and dialysis dependence were the primary outcome measures, while change in creatinine and urea, plasma levels of inflammatory mediators, and treatment emergent adverse events were the secondary outcome measures. Two authors (R.C., N.N.) independently assessed the quality of randomized controlled trials by using the Cochrane risk of bias tool for RCTs [13] and Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized controlled trials [14] (Tables 3, 4). Any disagreement between the two authors was resolved through discussion with the third author (R.R.). In the random sequence generation, all but the Meng and Miao study were at low risk of selection bias; in the allocation concealment, three studies had a risk of bias; in blinding of participants and personnel, none of the four studies were at low risk, no trial either blinded which patients participated in what trial or was it retrospective in nature; in blinding of outcome assessment, none of the studies were at low risk; and in incomplete outcome data, all four studies had low risk of bias.

Table 3.

Risk bias chart for randomized controlled trials

 Risk bias chart for randomized controlled trials
 Risk bias chart for randomized controlled trials
Table 4.

Assessment of the quality of the studies analyzed by the NOS

 Assessment of the quality of the studies analyzed by the NOS
 Assessment of the quality of the studies analyzed by the NOS

Data Synthesis

We combined data from studies with similar designs, interventions, and corresponding outcomes. We used a random effects model to measure treatment effects of dichotomous variables. Heterogeneity was assessed using an I2 test. In cases of high heterogeneity (>50%), we tried to explore the cause by performing the following subgroup analysis:

  • Exposure type (Sepsis vs. MODS)

  • Setting (single center vs. multicenter)

  • Type of study (RCTs vs. non RCTs)

Additionally, each study was analyzed for a variety of factors related to the progression of sepsis, with each variable being statistically analyzed. Data points pulled for analysis included mortality from sepsis and/or hemophagocytic lymphohistiocytosis (HLH), serum creatinine at 24, 48, and 72 h, hypokalemia, hyperkalemia, bleeding, hypernatremia, hyponatremia, and hyperglycemia.

Statistical Analysis

Data were analyzed using the RevMan 5.3 software. A risk ratio (RR) with 95% confidence interval (CI) was used for analysis of the primary and secondary outcomes. A summary of the statistical data was conducted using a forest plot. p value and I-square statistic (I2) were used to help determine heterogeneity in the pooled analysis of the results. These statistics help to assess the total variation across the studies by percentage.

Finally, the efficacy of the systemic review was conducted using the NIH Study Quality Assessment Tool (Table 5). A PRISMA checklist for the systemic review is provided in online supplementary Table 1 (see www.karger.com/doi/10.1159/000520519 for all online suppl. material).

Table 5.

NIH study quality assessment tool

 NIH study quality assessment tool
 NIH study quality assessment tool

Results of the Literature Search

After the initial search, 1,623 articles were identified with 223 removed due to duplications. We excluded all articles that were literature reviews, animal studies, systematic reviews, and abstract-only articles. Of the remaining 1,400 articles, 1,300 were excluded based off the titles and abstracts. Another 87 articles were excluded in accordance with our eligibility outcomes as defined within our PICO chart (Table 1). Of the remaining articles, 4 were selected that fit all the desired criteria that included 304 patients between 2015 and 2020. All the studies collected were conducted in Asia. The PRISMA flowchart showing studies for inclusion is shown in Figure 1 [29]. Our analysis concentrated on the effect of HVHF in sepsis and HLH with four studies qualifying for quantitative synthesis; Cui et al. [15], Miao et al. [16], Meng et al. [17], and Ning et al. [18]. Of note, Cui et al. [15] did not utilize renal replacement therapy in their control group. All other studies analyzed either did not incorporate pediatric data or had too few variables in which to compare and analyze.

Fig. 1.

PRISMA flowchart showing studies considered for inclusion.

Fig. 1.

PRISMA flowchart showing studies considered for inclusion.

Close modal

HVHF Settings and Comparisons

Each of the four studies identified reported settings for HVHF effluent rate, with a range of 50–100 mL/kg/h. Cui et al. [15] and Miao et al. [16] studied their patients using a rate of 50–70 mL/kg/h, while Ning et al. [18] applied a rate of 60/mL/kg/h and Meng et al. [17] studied their patients over the largest range of 50–100 mL/kg/h. Each study similarly compared the results of HVHF to the standard use of continuous venovenous hemofiltration (CVVH) to evaluate feasibility. Three of the studies, Cui, Ning, and Meng, found HVHF to be superior to that of CVVH in clearing cytokines and improving mortality. Miao et al. [16] did not find a significant difference in the results between both interventions.

All-Cause Mortality

All four studies with a total of 304 participants reported this outcome. Three studies were conducted in children with sepsis (Meng, Miao, and Ning) and one was conducted in children with HLH (Cui). Overall, HVHF in children with sepsis reduced all-cause mortality by 40% (RR: 0.60; 95% CI: 0.39–0.93; 2 studies; 278 participants; I2 = 4%) (Fig. 2). In children with HLH, no significant mortality benefit was observed in those undergoing HVHF as compared to controls (managed by the conservative method only) (RR: 0.52; 95% CI: 0.22–1.23; 1 study; 33 participants). On performing sensitivity analysis by excluding the nonrandomized trial (Miao), the results remained in favor of HVHF (RR: 0.41; 95% CI: 0.19–0.85; 2 studies; 123 participants; I2 = 0%). Statistical analysis was conducted on all studies along with additional analysis on only the prospective studies pooled together (Fig. 2, 3).

Fig. 2.

Pooled statistical analysis of mortality in HVHF use among all four studies. CI, confidence interval; HVHF, high-volume hemofiltration.

Fig. 2.

Pooled statistical analysis of mortality in HVHF use among all four studies. CI, confidence interval; HVHF, high-volume hemofiltration.

Close modal
Fig. 3.

Pooled statistical analysis of mortality in HVHF use among the prospective studies. CI, confidence interval; HVHF, high-volume hemofiltration.

Fig. 3.

Pooled statistical analysis of mortality in HVHF use among the prospective studies. CI, confidence interval; HVHF, high-volume hemofiltration.

Close modal

Serum Creatinine Levels within Initial 72 h

Two studies reported this outcome (Ning and Miao). One study (Ning) reported serum creatinine at 24 h and 48 h, whereas both studies reported serum creatinine at 72 h (Ning and Miao). Overall, the pooled estimate showed a significant reduction in serum creatinine at 24 h (MD: −50.00; 95% CI: −99.04, −0.96, 1 study; 47 participants); 48 h (MD: −65.60; 95% CI: −109.48, −21.72; 1 study; 47 participants), but no significant decrease in serum creatinine at 72 h (MD: −36.15; 95% CI: −88.12, 15.81; 2 studies; 202 participants; I2 = 87%) (Fig. 4). Cui et al. [15] did not report serum creatinine in both groups and hence the results could not be pooled for this analysis.

Fig. 4.

Statistical analysis of serum creatinine clearance at 24, 48 and 72 h. CI, confidence interval; HVHF, high-volume hemofiltration.

Fig. 4.

Statistical analysis of serum creatinine clearance at 24, 48 and 72 h. CI, confidence interval; HVHF, high-volume hemofiltration.

Close modal

Duration of ICU Stay and Therapy

One study reported the duration of ICU stay (Miao), which was shorter in patients undergoing HVHF (MD: −3.70; 95% CI: −7.05, −0.35; 1 study; 155 participants). Another study reporting duration of treatment course revealed a significant decrease in treatment course in the HVHF group (MD: −1.20; 95% CI: −1.84, −0.56) (Meng).

Cytokine Clearance

Three of the studies, Ning, Miao, and Meng, reported the efficacy of cytokine clearance by HVHF compared to CVVH. Biomarkers that were studied by all three studies were pooled together for analysis. The difference in the cytokine level before and after 72 h of treatment is shown in Table 6. The cytokines analyzed were IL-6 and TNF-a. For IL-6, a significant difference in the reduction ratio between CVVH and HVHF was found in the studies by Ning and Meng (12.7% vs. 60.4% and 33.3% vs. 57.1%, respectively). No significant difference was found in IL-6 clearance by Miao (53.6% vs. 49.3%). For TNF-a, a significant reduction ratio was found between CVVH and HVHF in the studies by Ning and Meng (14.2% vs. 57.5% and 27.2% vs. 57.6%, respectively), with the percentage being lower in CVVH. Similar to the IL-6 results, the study by Miao did not find a significant difference between CVVH and HVHF for TNF-a clearance (38.7% vs. 49.4%) (Table 6).

Table 6.

Cytokine clearance of HVHF versus CVVH as reported by the studies analyzed

 Cytokine clearance of HVHF versus CVVH as reported by the studies analyzed
 Cytokine clearance of HVHF versus CVVH as reported by the studies analyzed

Adverse Events

All studies reported adverse events in two groups. The results from two studies were pooled (Miao and Cui) and the pooled estimate showed no difference in the proportion of patients developing hypokalemia (RR: 1.01; 95% CI: 0.65, 1.56; 2 studies; 188 participants; I2 = 0%) (Miao and Cui); hyperkalemia (RR: 0.83; 95% CI: 0.35, 1.99; 1 study; 155 participants) (Miao), hypernatremia (RR: 1.56; 95% CI: 0.76, 3.17; 1 study; 155 participants) (Miao), or hyponatremia (RR: 1.62; 95% CI: 0.71, 3.67; 1 study; 155 participants) (Miao). The proportion of patients developing hyperglycemia was higher in patients undergoing HVHF (1.42; 95% CI: 1.13, 1.80; 2 studies; 188 participants) (Miao and Cui), whereas the proportions of patients developing bleeding was significantly less in patients undergoing HVHF (RR: 0.38; 95% CI: 0.17, 0.85; 1 study; 155 participants) (Fig. 5). Meng et al. [17] reported the total number of adverse events between the two groups, which were significantly decreased in patients undergoing HVHF (RR: 0.43; 95% CI: 0.18, 1.00; 76 participants) (Meng).

Fig. 5.

Pooled statistical analysis of secondary endpoint and complications of HVHF and CVVH. CI, confidence interval; CVVH, continuous venovenous hemofiltration; HVHF, high-volume hemofiltration.

Fig. 5.

Pooled statistical analysis of secondary endpoint and complications of HVHF and CVVH. CI, confidence interval; CVVH, continuous venovenous hemofiltration; HVHF, high-volume hemofiltration.

Close modal

Sepsis in Pediatric Patients Is a Critical Public Health Issue due to Its High Mortality

Severe sepsis works through the excess release of inflammatory mediators and cytokines. These cytokines can lead to subsequent multiple organ dysfunction and systematic inflammatory response syndrome if not cleared in time. CKRT has shown to be beneficial in clearing these inflammatory markers due to their ability to accurately manage fluid load [8]. To facilitate faster clearance of cytokines and reduce stay in hospital, higher CKRT flux rates have been investigated. In adults, the use of higher CKRT flux rates (>35 mL/kg/h) in filtration dialysis has not shown to have a significant benefit in reducing overall mortality benefit in available RCTs and meta-analysis [12]. While no consensus has been reached on the therapeutic volume for HVHF, in children a continuous hemofiltration replacement fluid rate of >50 mL/kg/h is considered acceptable.

In our literature review, we identified four studies discussing the significance of HVHF use in sepsis and HLH. HVHF has shown promising results in patients with elevated cytokine/inflammatory markers. Nevertheless, none of the studies analyzed were a large multicenter randomized control trial that could provide more data on the safety and efficacy of use of HVHF in comparison to other modalities in the pediatric population. Based on the few studies, we discovered that the use of HVHF has shown possible beneficial effects on reducing mortality and improvement of secondary endpoints.

Examining the results sequentially, we looked at the differences in the HVHF settings. While the paucity of data limits the ability to draw significant conclusions as far as HVHF settings are concerned, all the studies conducted their observation or analysis within an effluent range of 50–100 mL/kg/h. Specifically, three different settings were used, 50–70, 60, and 50–100 mg/kg/h, with each showing overall survival benefit and significant reduction of inflammatory cytokines and serum creatinine. Of note is the difference in results between Cui et al. [15] and Miao et al. [16], who used the same parameters in their analysis. Miao et al. [16] did not find a significant benefit in HVHF usage with a study population more than twice (155 vs. 72) the size of Cui et al. [15]. However, Cui et al. [15] was a prospective study, whereas the Miao study was retrospective in nature. Even accounting for potential bias sources and missing data from the retrospective analysis by Miao et al. [16], it warrants further investigation to further narrow down the optimal range necessary for the pediatric population.

Looking at arguably the most significant outcome, 28-day mortality, most studies found benefit in using HVHF. All-cause mortality was reduced by 40%, though no significant effect was seen in children receiving treatment for HLH versus sepsis. The largest study (n = 155) by Miao et al. [16] found that there was no significant difference in the 28-day mortality rate between the two groups (p = 0.467). In the group studied by Meng et al. [17], a total of 10 (26.3%) deaths were recorded in the CVVH group versus three (7.9%) in the HVHF, whereas, in the Ning study, there was no significant difference in 28-day mortality between the CVVH group and the HVHF group (χ2 = 2.446, p = 0.201). To improve and confirm the significance of the potential survival benefits, larger study populations will be required in future prospective studies. Though based on these preliminary results, it does hold promise that HVHF can provide a net neutral benefit for mortality while still providing a significant benefit for other secondary endpoints.

In regard to the survival benefit seen, much of it may be attributed to the rate and efficacy in drawing out inflammatory biomarkers and reducing serum creatinine. When looking at serum creatinine, there is a significant reduction of serum creatinine at both 24 and 48 h post enrollment of the patient; however, these benefits did not extend to observations after 72 h. In children, HVHF implementation can help to reduce the fluid overload due to fluid resuscitation along with the removal of excess metabolites and biomarkers such as creatinine and urea in an efficient manner. In the previously conducted retrospective study, CVVH in pediatric patients with light fluid overload showed an increased survival rate. The benefit was especially pronounced in patients that had MODS [19].

When examining the removal of inflammatory cytokines, there is a significant decrease found in both IL-6 and TNF-a in two out of the three studies that recorded this variable. This may indicate that circulating cytokines were more efficiently removed when CKRT was applied at a volume higher than that administered under standard care. Through previously published animal models and clinical trials of sepsis, it confirms that by using a high-biocompatibility and high-permeability filter, HVHF continuously clears multiple large and medium molecular inflammatory mediators, such as IL-1β, IL-6, IL-8, TNF-α, C3a, C5a, prostaglandin, leukotriene, active oxygen free radical, or platelet-activating factors [20].

Duration of ICU stay was a statistic variable that was lacking in most of the studies. Only the retrospective study by Miao et al. [16] reported a shorter stay for patients than CVVH. Previous studies in pediatric populations have found that long-stay (12–30 day) ICU patients have a higher risk of mortality (15–40%) and long-term morbidity. Long time of stay can be challenging due to increased risk of infection and the cost of ICU resources. The potential benefit of HVHF for clearing cytokines and serum creatinine in a timelier manner warrants more closer examination in future studies.

All studies reported adverse events for both HVHF and CVVH groups. Pooled results from Miao et al. [16] and Cui et al. [15] showed a significant benefit in the development hypokalemia, hyperkalemia, hypernatremia, or hyponatremia while showing increased development of hyperglycemia. Additionally, the rate of bleeding was significantly lower in the HVHF groups. In the nonpooled studies, Ning et al. [18] showed only 4 cases of complication, hypotension (n = 4), that was caused by excess removal of fluid. Meng et al. [17] found that complications of hypernatremia, alkali imbalance, and glucose abnormalities in the HVHF group are higher than that of the standard-volume CVVH group (p < 0.05 or p < 0.01). Given the small population size of these studies, it makes it difficult to derive a firm conclusion over HVHF ability to reduce adverse effects. These initial reports, however, warrant future studies with larger population samples to fully derive safety and efficacy.

One potential mechanism in which HVHF may be beneficial is in patients with inborn errors of metabolism. When present, especially with liver dysfunction, there is a decrease in hepatic clearance of protein by-products and amino acid breakdowns [21], leading to accumulation of ammonia. Hyperammonemia can cause inflammatory cytokine release, cerebral edema, severe disability, and death [22]. Several studies have emphasized a beneficial effect for the use of HVHF in hemodynamically unstable with higher ammonia level patients [23‒26]. A previous retrospective study by Lai et al. [27] conducted on 8 patients with acute neurological deterioration due to ammonia or organic acid accumulation. Various modalities of KRT, such as CVVHD, HD, and PD, were used in this pediatric population. When results were compared among the different modalities, high-volume CVVH (>35 mL/kg/h) demonstrated more effective elimination of ammonia and other organic acids in pediatric patients than others [27]. Likewise, in a study by Spinale et al. [28], two neonates with hyperammonemia received high-dose CKRT, of which one was hemodynamically unstable. Both patients showed a significant recovery and a decrease in ammonia levels within 2- to 7-h duration. CKRT showed a decreased risk of ammonia rebound due to continuous clearance compared to intermittent hemodialysis [28]. The studies utilized for analysis in this study did not contain information on inborn errors of metabolism, and as such, it could not be analyzed, but it was felt important to discuss and highlight as another potential avenue of research and treatment for this modality.

In conclusion, HVHF shows some promise as a modality to treat sepsis in the patient population. It shows a potential benefit in 28-day mortality, cytokine and creatinine clearance, and adverse effects. Any recommendation for its use, however, is hampered by the lack of large randomized controlled trials. With future studies with larger study populations, a full health and safety profile can be constructed that allows for accurate comparison to the current standard of care.

The authors would like to acknowledge Nirav Agarwal for his assistance in developing the search criteria and the initial analysis of data for the project.

An ethics statement is not applicable because this study is based exclusively on the published literature.

The authors have no conflicts of interest to declare.

This manuscript did not receive grants from any funding agency in the public, commercial or not-for-profit sectors.

N.N., R.R., G.C.B., and S.S. worked to conceptualize the direction of the manuscript. I.M., N.N., and R.C. all worked on the literature search. G.C.B., B.S., S.S., S.S., and R.R. worked on the statistical analysis of the data set gathered. K.G., N.K., N.N., R.R., and G.C.B. worked to write the initial manuscript. Each author had a role in reviewing and editing the final manuscript. Figures and tables were created by G.C.B., N.N., and I.M.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further enquiries can be directed to the corresponding author.

Additional Information

Girish Chandra Bhatt and Sidharth Kumar Sethi are co-first authors.

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