CASE SCENARIO

59 yo male with a PMHx of chronic kidney disease, hypertension, DM type II, presents to ED for altered mental status. Patient’s daughter explains that he experienced signs of delirium for the past 2-3 days. Lab values show leukocytosis with positive urine analysis and positive blood cultures. Patient’s vitals indicate tachycardia, fever of 100.1 degrees fahrenheit. Patient is also due for hemodialysis treatment.

SEARCH QUESTION :

Should hemodialysis be initiated at a higher rate treatment in septic adult patients to improve mortality rates?

QUESTION TYPE : 

Prevalence Screening Diagnosis

Prognosis Treatment Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices. 

For this PICO search, I would prioritize meta-analysis or systematic review as they are regarded as the highest level of study and include several already existing peer-reviewed studies. If meta-analysis or systematic review are not available, I would expand my search to include retrospective cohort studies to analyze past outcomes on the relationship between the timing of antibiotic treatment and hemodialysis in septic patients.  Retrospective cohort studies allow for a pooling of a large amount of data that already exists. I would also include randomized control trials in my search as a control group who received high volume filtration versus standard volume filtration can assess the benefit of this technique on septic patients. However, the RCT would have to implement tight inclusion and exclusion criteria as well as standardized delivery of filtration to ensure confounding factors do not influence results.  

PICO SEARCH TERMS :

P	I	C	O
Septic elderly patient	High volume hemodialysis	Low volume hemodialysis	Lower mortality
Bacteremia elderly patient	Higher volume hemodialysis	Standard volume hemodialysis	Reduced deaths
Elderly patient with sepsis	High rate hemodialysis	Standard rate hemodialysis	Improved mortality

SEARCH TOOLS & STRATEGIES USED :

Please indicate what databases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters. 

For this PICO search, I included systematic reviews, meta-analysis, and randomized controlled trials. The use of filters for these specific studies as well as a ten-year period limit significantly reduced the number of results to better search for qualified studies. Three of the four studies found pertained to the PICO clinical case studied in that it specifically looked at high volume hemofiltration in septic patients. However, I chose to include a fourth study that added an additional layer with septic patients who also experienced burns. In doing so, I may have a greater perspective of how HVFH can be used in more than one type of septic-presenting patient. When practicing medicine, it is important to consider that although a treatment may not work in one patient demographic, it may prove to be useful for other patient presentations. 

Database	Filter	Terms Searched	Articles Returned
PubMed	Meta- AnalysisSystematic ReviewCohort Studies2012 – 2022	Sepsis hemodialysis timing	35
Sepsis hemodialysis delay	14
JAMA	Research ReviewSurgery	Sepsis hemodialysis timing	16
Sepsis hemodialysis delay	10
Cochrane	Review	Sepsis hemodialysis timing	1
Sepsis hemodialysis delay	2

RESULTS FOUND :

Article 1 : High‐volume haemofiltration for sepsis in adults

Citation: Borthwick EMJ, Hill CJ, Rabindranath KS, Maxwell AP, McAuley DF, Blackwood B. High-volume haemofiltration for sepsis in adults. Cochrane Database of Systematic Reviews. 2017;2018(12). doi:10.1002/14651858.cd008075.pub3

Type of Study: Systematic Review

Abstract: In the intensive care unit, sepsis and septic shock are leading causes of death. For this reason, optimal management in the type and timing of treatment is crucial to ensure low mortality rates in patients. This study aims to determine if the use of high-volume hemofiltration can improve outcomes in septic ICU patients.

Methods :This systematic review was performed in 2017 and included randomized controlled trials. Three independent reviewers were used to assess study quality and extract data.  The following databases were used to search for eligible studies:Cochrane Central Register of Controlled TrialsMEDLINEEmbaseLatin American Caribbean Health Sciences LiteratureWeb of Science and Cumulative Index to Nursing and Allied Health Literature This study screened specifically for studies that compared the use of high volume filtration versus standard volume filtration in septic patients in the ICU to see if higher filtration rates improved mortality rates and patient outcome.

Results :Four randomized controlled trials with a total of two-hundred participants. Two of these trials reported 28-day mortality rates and one trial studied hospital mortality outcomes. The last study looked at hemodynamic status, inflammatory mediator concentrations, and organ dysfunction scores.  The first study showed that there was a 33.3% ICU mortality rate in high volume filtration vs 60% standard filtration rate (RR 0.59, 95% CI [0.19-1.59]). The second study reported an ICU mortality rate of 37.9% ICU mortality rate in high volume filtration vs. 40.8% mortality in standard filtration (RR 0.67, 95% CI [0.22-2.03]). The third study that looked at hospital mortality rates was a cross-over study and yielded inconclusive results as comparison was not possible. The last study reported a 76% mortality rate but had discrepancies between the number or deaths reported and mortality rate. For this reason, this study also yielded inconclusive conclusions for this study.

Reason for Selection: This study was selected as it was a systematic review performed in the last five years. This represents a high-level of study with recent data and results. Furthermore, the study looked specifically at ICU septic patients. As patients are severely ill, this study has a stronger selection of patients to observe for improved or reduced rates of mortality with high volume hemodialysis intervention.

Conclusion :This study found no adverse effects related to high volume hemodialysis filtration. However, the study addresses that there were a low number of participants. For this reason, it is unable to make a definitive recommendation of using high volume hemodialysis filtration in critically ill patients.

Key Points:High filtration volume rates demonstrated a lower mortality rate compared to standard filtration rate in the ICU setting for septic patientsThis study could not make definitive recommendations on the use of high volume filtration rate to reduce mortality due to low number of participants

Article 2 – High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis

Citation: Clark E, Molnar AO, Joannes-Boyau O, Honoré PM, Sikora L, Bagshaw SM. High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis. Crit Care. 2014 Jan 8;18(1):R7. doi: 10.1186/cc13184. PMID: 24398168; PMCID: PMC4057068.

Type of Study: Systematic Review & Meta Analysis

Abstract: In patients with septic acute kidney injury, the discussion of the use of high-volume hemofiltration presents an attractive solution with potentially beneficial outcomes. Smaller studies have suggested higher survival rates in patients who receive HVFH (high volume filtration hemofiltration). This study compares the use of HVHF and standard volume hemofiltration in patients with septic AKI to determine which treatment method offers lower mortality rates.

Methods :This systematic review and meta-analysis was performed in 2014 and included randomized controlled trials. Results were assessed based on a 28-day mortality rate. This study also assessed kidney function, length of ICU stay, length of hospital stay, reduction in vasopressor dose, and other adverse events. Studies were assessed by two independent reviewers.  The following databases were used to screen for studies:Cochrane Database of Systematic ReviewsDatabase of Abstracts of Review of EffectsCochrane Central Register of Controlled TrialsMedlineEmbase Inclusion Criteria:Randomized Control TrialsICU patientsAge > 18 yoSepsis/Septic Shock DiagnosisTreatment of HVHF with > 50 ml/kg/hr infusion rateReports on mortality rate Exclusion Criteria:Observational StudiesQuasi-Randomized StudiesCrossover StudiesCase ReportsCase SeriesReview ArticlesNeonatal & Pediatric PopulationPost-Cardiac Surgery Population

Results : Four trials with a total of 470 total participants were included in this study. There was no substantial difference between HVHF and standard volume hemofiltration over the course of a 28-day period (OR 0.76, 95% CI [0.45-1.29]). HVHF patients were found to experience higher rates of hypophosphatemia and hypokalemia. However, this was not a consistent finding across all four studies. Patients who received HVHF were found to have a 75% reduction in norepinephrine dose (RR 2.22, 95% CI [1.01 – 4.51]). No significant differences were found between ICU and hospital length of stay between HVHF and standard rate filtration patients. Patients who had HVHF experienced lower core temperatures.

Reason for Selection: This study was a systematic and meta analysis performed within the last 10 years to yield current and high-levels of study. The study also looked specifically at AKI patients and pertains to the clinical case scenario patient presented in this PICO case. This study also looked at adverse effects in HVHF patients and length of hospital stay as well as mortality rates to provide a more holistic picture of the benefits and harms in this treatment method.

Conclusion : This study ultimately concluded that there is insufficient evidence to suggest that the use of HVHF for septic AKI demonstrated greater therapeutic benefits.

Key Points:No significant difference found in mortality rates between HVHF and standard filtration rate patientsNo significant difference found in hospital length of stay between HVHF and standard filtration rate patientsHigher incidences of hypophosphatemia and hypokalemia in HVHF patients\HVHF patients experienced greater rates of lower core temperature

Article 3 – Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomized controlled trial

Citation: Joannes-Boyau O, Honoré PM, Perez P, Bagshaw SM, Grand H, Canivet JL, Dewitte A, Flamens C, Pujol W, Grandoulier AS, Fleureau C, Jacobs R, Broux C, Floch H, Branchard O, Franck S, Rozé H, Collin V, Boer W, Calderon J, Gauche B, Spapen HD, Janvier G, Ouattara A. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013 Sep;39(9):1535-46. doi: 10.1007/s00134-013-2967-z. Epub 2013 Jun 6. PMID: 23740278.

Type of Study: Randomized Control Trial

Abstract: A leading cause of death among critically ill patients is often due to sepsis or septic shock. This presentation is exacerbated by the presence of acute kidney injury. For this reason, this randomized control trial aims to look at high-volume hemofiltration methods to see if they reduced mortality rates in critically ill patients with septic shock and AKI. High volume filtration hemodialysis offers promising benefits in maintaining acid-base balance, fluid homeostasis, and removal of toxins and inflammatory mediators.

Methods :This randomized control trial was performed across 18 ICUs in France, Belgium, and the Netherlands. A total of 140 participants were studied. Patients who received HVFH were placed on 70 ml/kg/hr and patients who received standard volume filtration were placed at 35 ml/kg/hr over a 96 hour period. Patients received hemodialysis through a continuous veno-henous hemofiltration mode. All patients received unfractionated heparin. Observations were made based on a 28 day study using SOFA score and mortality rates.  Inclusion CriteriaAge > 18yoAdmission to ICU Presence of Septic ShockPresence of AKI

Results : A total of 137 participants were studied. 66 of these patients received high filtration whereas 71 received standard filtration. The results showed that there was no significant difference in mortality rate at 28 days between both filtration methods (RR 5.52, CI 95% [0.65-47.28]). HVFH showed a 37.9% mortality rate whereas standard filtration exhibited a 40.8% mortality rate.

Reason for Selection: This study was chosen as it was a randomized control trial performed within the last 10 years to offer current treatment options and results. Furthermore, the study contained tight controls on the delivery of hemodialysis, type of instrument used, and anticoagulation. This minimized confounding factors that could have skewed results. Additionally, all patients were critically ill, experienced septic shock, and had AKIs. This pertains to the patient presented in the clinical case scenario to help make a stronger assessment for the PICO study at hand.

Conclusion : This study found that there was no difference found in the use of HVHF at 70 ml/kg/hr in reducing mortality rates in septic AKI patients compared to standard filtration at 35 ml/kg/hr. For this reason, the study cannot conclusively recommend the use of HVFH in this patient demographic to improve outcomes.

Key Points:HVFH did not reduce 28-day mortality rate compared to standard volume hemofiltration

Article 4 – High-volume hemofiltration in adult burn patients with septic shock and acute kidney injury: a multicenter randomized controlled trial

Citation:Chung KK, Coates EC, Smith DJ Jr, Karlnoski RA, Hickerson WL, Arnold-Ross AL, Mosier MJ, Halerz M, Sprague AM, Mullins RF, Caruso DM, Albrecht M, Arnoldo BD, Burris AM, Taylor SL, Wolf SE; Randomized controlled Evaluation of high-volume hemofiltration in adult burn patients with Septic shock and acute kidney injury (RESCUE) Investigators. High-volume hemofiltration in adult burn patients with septic shock and acute kidney injury: a multicenter randomized controlled trial. Crit Care. 2017 Nov 25;21(1):289. doi: 10.1186/s13054-017-1878-8. PMID: 29178943; PMCID: PMC5702112.

Type of Study: Randomized Controlled Trial

Abstract: Septic shock remains a leading cause of death in the hospital setting. Burn patients present with a greater risk due to a compromised hypermetabolic state. Patients in septic shock are also more likely to develop acute kidney injury as a consequence.

Methods :This randomized control trial was performed in 2017. Patients suffering from burns, septic shock, and AKI were given HVFHat a rate of 70 ml/kg/hr. Control patients received standardized filtration at rates determined by local practices. Participants received hemofiltration through the NxStage System One of PRISMAFLEX System. Anticoagulation strategies differed based on needs of the patient and assessment made by the treatment team.  Inclusion Criteria:Burn patientExperienced AKI 2 days post-burn (<20ml/hr urine output for >24 hours)Increased Serum CREAT >2mg/dl < 4 days in malesIncreased Serum CREAT >1.5 mg/dl < 4 days in females  Exclusion Criteria:End Stage Renal Disease patients

Results : In total, 28 patients were randomized and studied. 14 patients received HVFH and 14 received standard volume hemofiltration. Patients who received HVFH experienced decreased vasopressor dependency (p=0.007). Multiple organ dysfunction was assessed at 14 days. The HVFH group demonstrated lower scores (p=0.02). No significant differences were noted in changes in inflammatory markers, surviva, or adverse events.

Reason for Selection: This randomized control trial was included as it was performed within the last 5 years to offer current data and results. Furthermore, it had a stronger inclusion criteria compared to other studies to ensure patients were more uniform in presentation of AKI to better assess the effects of hemofiltration in this patient demographic. Finally, this study differed from the previous three in that it specifically looked at septic AKI patients suffering from burns. As the previous studies generated inconclusive results on the benefits of HVHF in septic patients, it is worth studying if septic patients with a more severe presentation may benefit from this treatment option.

Conclusion : This study suggests that HVHF was effective in improving organ function in burn patients suffering from burns and AKI. However, the study was hesitant to state that HFVH improved survival rates due to the small participant size and short-term study of the design.

Key Points:HVHF improved organ function in septic burn patients with AKIThere is no conclusive evidence that HVHF improved survival rates in septic burn patients with AKI

Weight of Evidence:

I would weigh Article 2 :  High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis as the strongest study. This was a meta-analysis that already included multiple established studies to draw a conclusion. In comparison to the other systematic study included in this PICO search, Article 2 included stronger inclusion and exclusion criteria to ensure that it was a more uniform participant demographic with standard delivery of HVFH to ensure that HVFH was the control studied in the trial. 

Next, I would select Article 1: High‐volume haemofiltration for sepsis in adults, as the next strongest study. This was a systematic study that included four studies that evaluated mortality rate from multiple viewpoints : ICU mortality rate and hospital mortality rate. Although this offered a broader observation of mortality rate, it lacked stronger inclusion and exclusion factors included in Article 2. As a result, too many factors could have influenced results that make it difficult to assess the impact of HVFH. 

Article 3: Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomized controlled trial

presents as the next strongest study as it was a randomized control trial that did not include the participant size demonstrated in Articles 1 & 2.However, in comparison to the other RCT included in this PICO study, Article 3 ensured to look specifically at septic patients with AKI and aligned better with the patient presented in the clinical case scenario. 

Last, Article 4: High-volume hemofiltration in adult burn patients with septic shock and acute kidney injury: a multicenter randomized controlled trial, presents as the weakest study. Article 4 offered insightful perspective on the benefits of HVFH in septic patients with additional presenting factors. However, it was a smaller participant in comparison to Article 3 and deviated slightly from the clinical case scenario. For this reason, Article 4 is important to provide a broader perspective on the use of HVFH in septic patients but does not as specifically address the clinical case scenario compared to the other articles. 

What is the clinical “bottom line” derived from these articles in answer to your question?

The clinical bottom line is that high volume hemofiltration cannot be recommended to reduce mortality rate in adult septic patients. Only two of the four studies showed benefits in using HVHF. However, they both addressed shortcomings to the design of their study in a low number of participants. For this reason, even though the studies showed promising results, they could not make a definitive recommendation that can be applied to the general population. Ideally, a longer-term study with a large number of participants, standardized filtration method, anticoagulation treatment, and measurement of outcomes is needed to assess the impact of HVHF in septic patients. Some adverse effects of HVHF such as electrolyte imbalance and lower core body temperature were also reported and would cause me to hesitate to definitively advise its use in already susceptible septic patients. These consequences could carry a greater risk of harm than benefit. HVHF did show promising results in burn patients with AKI and sepsis in a randomized control study. For this reason, I would also not completely rule out the use of HVHF in patients with a severe presentation. In these patient cases, all treatment options should be exhausted to try to reverse septic shock. I would reserve HVHF for patients with dire presentations where standard septic shock treatment is inadequate.