Hemoperfusion: An Innovative Adsorption Technology for Multi-Organ Failure

Prof. Romina A. Danguilan, MD

Head of Hemodialysis Unit, National Kidney and Transplant Institute, Philippines

1.    Leptospirosis introduction

Leptospirosis is a bacterial disease that results in exposure of mucous membranes to the urine of infected animals, usually rats in urban cities. The most severe complication is Weil’s disease while patients would suffer from jaundice, renal failure, and pulmonary hemorrhage. Leptospirosis presenting with renal failure is often accompanied by pulmonary hemorrhage and carries high mortality despite standard therapy. In a review of 194 patients suffering from Leptospirosis, 25% of patients died and are mostly due to pulmonary hemorrhage, sepsis, or multiple organ failure. Significant predictors of mortality of leptospirosis are low platelet count, prolonged prothrombin time, and parenchymal infiltrates on chest X-ray.

2. The role of hemoperfusion in sepsis management of leptospirosis

According to the inflammatory mechanisms in sepsis, the cytokines storm plays an important part in the disease progress. Both the occurrence and management of cytokine storms are closely related to the immune response behavior. While the pro-inflammatory arm reaches the peak (Phase B in the Picture), it would be likely to gain the maximal benefits from extracorporeal therapy. For severe leptospirosis patients, ECMO is conducted for pulmonary hemorrhage, while HA330 hemoperfusion plus RRT is conducted for sepsis in the treatment protocol. The experience shows that hemoperfusion on patients with severe leptospirosis with renal failure and pulmonary hemorrhage is a useful method to support the management of AKI in critically ill patients. The results turned out that:

1) 30% mortality among patients with pulmonary hemorrhage and dialysis –dependent AKI.

2)  The SOFA scores significantly decreased by the 3rd HP

3)  Procalcitonin significantly decreased by the 3rd HP

4)  Inotropes were tapered to off by the 1st HP

By improving the organ function, stabilizing the hemodynamic and controlling the inflammatory status, HA330 hemoperfusion cartridge is useful to prevent complications in these patients with multi-organ failure.

3. HA330 hemoperfusion therapy in COVID-19

Indications for Hemoperfusion for HA 330 are CXR - multilobar or diffuse infiltrates PLUS Any one of the following such as increasing Ferritin, increasing LDH, lymphopenia, High D- Dimer, Increasing HsCRP, etc. HA330 hemoperfusion is based on 4 cartridges therapy while on Day 1 there are 2 cartridges every 12 hours apart and on Day 2& 3 each day 1 HA330 cartridge. Patients are commonly seen on hemodialysis with hemoperfusion because it is a kidney department with ESRD patients. Duration for hemoperfusion is 3 hours. The blood flow rate is 250 ml/min and low dose heparin is used for anticoagulation. For non-ESRD and PD patients, the central line was inserted for the therapy. Outcomes of five patients showed that HsCRP, ferritin, and LDH decreased and lymphocytes increased after the 4 cartridges hemoperfusion therapy. CXR improvements were observed in both single hemoperfusion and hemoperfusion combined with tocilizumab cases.

Haemoperfusion: A Promising Extracorporeal Blood Purification therapy in improving the ICU outcomes of critically ill patients with COVID-19

Dr. Liang Yu, MD

Infectious Disease Department, The First Hospital of Zhejiang Province, China

Dr. Liang Yu reported his clinical research on hemoperfusion safety and efficacy on COVID-19 patients after a brief introduction of COVID-19 situation and the Zhejiang experience from China, in which the treatment strategy centered on the “Four-Anti and Two-Balance” strategy to effectively increase the cure rate and reduced mortality. Since shock and hypoxemia are usually caused by cytokine storms, the artificial liver support system (ALSS) and blood purification can effectively diminish inflammatory mediators and cytokine cascade and prevent the incidence of shock, hypoxemia and respiratory distress syndrome.

In this clinical research, 47 confirmed COVID-19 critically ill patients were included and divided into two groups; one is conventional treatment group while patients receiving oxygen support, anti-viral agents, probiotics, glucocorticoids, etc. and the other is HA hemoperfusion treatment group while patients receiving HA hemoperfusion based on the conventional treatment. Hemoperfusion was conducted once a day for 3 consecutive days, and each session lasted for 3 hours. The parameters such as APACHE-II score, pneumonia severity index (PSI), ARDS severity, cytokine levels, invasive positive pressure ventilation (IPPV) duration, length of ICU stay, and 28-day mortality rate were investigated. Result shows that

1)  There was a significant decrease of serum IL-6, IL-10, TNF-α, and IFN-γ after HA treatment compared with the conventional treatment group; Three consecutive treatments of HA type haemoperfusion were effective in improving oxygen supply and contributed to the reduction in disease severity scores including the APACHE-II score and PSI.

2) Benefits were showed in the HA hemoperfusion treatment group about mortality, ICU free days, fatal or patient in need of ECMO support with a significant difference.

3)  Also, HA treatment showed no significant difference in the incidence of safety measures including total white cells, hemoglobin, platelets, international normalized ratio, etc. compared with the control group.

Usage of HA330 (Sepsis Column) in the ICU for COVID-19

Prof. ERDAL KURTOĞLU, MD

Head of the hematology department

University of Health Sciences Antalya Training and Research Hospital, Turkey

Based on the rational evidence supporting hemoperfusion for COVID-19 patients, Prof. ERDAL KURTOĞLU shared his experience using HA330 for COVID-19 patients in the ICU.

1)  For anticoagulation: Both heparin and citrate are recommended; heparin dosage may exceed the necessary for hemodialysis due to hypercoagulable state of COVID-19 patients or heparin adsorption and ACT should be maintained at app. 2-2.5 times normal or an APTT of the app. 60-70 seconds.

2)  For treatment setting: Optimal blood flow is about 300 ml/min, it can be increased to 450 ml/min. Intermittent hemoperfusion is performed for 4 hours.

3)   For COVID-19 cases: For 7 patients (Aged from 53-86, 5 males and 2 females), patients received 3-8 HA330 cartridges with a median of 5. The result shows 3 recoveries, among whom 5-8 HA330 cartridges were given for hemoperfusion therapy.

4)  Attentions: Patients with the age below 60 showed better results; IL level is important for evaluation; coagulation and catheter problems are worth attention.

DISCUSSION

1. Timing to start hemoperfusion

- Dr. Liang Yu

The purpose of hemoadsorption is to remove inflammatory mediators from the circulation, and the start of HA treatment should not be determined by whether there is AKI. When we found a patient with rapidly progress of lung lesions or persistently elevated level of cytokine then we started the treatment. There was an expert consensus on Application of artificial liver and blood purification system in the treatment of severe and critical COVID-19 1, which has been published and you can find more information in it. Also, it would be late if the patient developed hypotension. In our center we didn’t have that much patients in shock with COVID-19.

- Prof. ERDAL KURTOĞLU

Firstly, the clinical condition of the patient is very important. Secondly, the Lung CT scan is also important. If possible, the level of cytokine is another indicator.

2.  Choice of extracorporeal organ support for organ dysfunction

- Dr. Liang Yu

In our study, we only conducted HA type hemoperfusion for the patients, but during H7N9 influenza in 2017, we performed a clinical trial of plasma exchange for critically ill patients. However, in china the blood source is always a problem, that’s why we choose HA type hemoperfusion during COVID-19.

- Prof. ERDAL KURTOĞLU

Hemoperfusion can be performed on many devices for patients, while apheresis is also necessary if you don’t have fitted equipment or materials. Plasma exchange can be effective as another choice when patients have DIC, hemodynamic or anticoagulated problems, unless the patient is in terminal position.

3. Anticoagulation for COVD-19 patients

- Dr. Liang Yu

We gave dairy anticoagulation for every COVID-19 patient, because according to the guideline 2 in China, anticoagulation was suggested for micro-thrombosis in the lungs. The dosage and duration is up to the coagulation function test.

- Prof. ERDAL KURTOĞLU

I didn’t follow all the COVID-19 patients in the ICU, but for COVID-19 patients under hemoperfusion, we used heparin as anticoagulant for unexpected thrombosis or bleeding, such as DIC in COVID-19 patients.

4. Rebound issue after hemoperfusion and how to solve the problem?

- Dr. Liang Yu

In my study, the condition of most patients in HA treatment group continue to improve without rebound, while in other study, the rebound can be observed in both control and hemoperfusion groups. I think this kind of rebound may be related with other condition such as bacterial coinfection or other complications. My experience is to use antibiotics in certain condition.

Q&A

1. The use of Tocilizumab for COVID-19?

- Prof. ERDAL KURTOĞLU

Tocilizumab is listed in the protocol in our country, and the doctors in the ICU are using it. It’s better not to use Tocilizumab and hemoperfusion at the same time but sequentially. You can use Tocilizumab first to block IL-6, then use hemoperfusion sequentially to remove others cytokines very fast from the blood stream.

- Dr. Liang Yu

We don’t use Tocilizumab to fight against IL-6 receptor. This drug only reduces the serum level of IL-6 and may cause an accumulation of circulating IL-6. With the inconsistent distribution of IL-6 receptors in the tissues, the elevated circulating IL-6 may affect more organs with high IL-6 receptor expression. As I know the results of the clinical trial of Tocilizumab in china may not be very good.

2. When should we start the hemoperfusion?

- Dr. Liang Yu

According to the expert consensus 1, when the elevated level of interleukin-6 in blood is more than 5 folds, it would be a start point. If you cannot test IL-6, you can measure with CRP, ferritin, or evaluating the lung lesion progress.

3. When should we stop the hemoperfusion?

- Prof. ERDAL KURTOĞLU

As least 3 cartridges should be performed. The parameters of hemodynamic, oxygenation, improvement of parameter if the patient is on mechanical ventilator, and IL-6 level are for the evaluation, while the clinical progress of the patient is the most important one. If you get the good result, you can increase the treatment dosage.

4. Does viral load measurement important before and after hemoperfusion?

- Dr. Liang Yu

We don’t think this is indicated for hemoperfusion therapy. In our center, we observed some patients with very long time viral positive period over 40 days. This maybe associated with the subtype of the viral, so we don’t think the viral load measurement would be indicated for hemoperfusion, or other therapies.

5. VV-ECMO or VA-ECMO for COVID-19 patients?

- Dr. Liang Yu

For patients without cardiac problems, we use VV-ECMO, others with VA-ECMO. The Average duration on ECMO is about 2 weeks in our center.

6. Antiviral drugs for COVID-19 patients?

-  Dr. Liang Yu

We used antiviral drugs according to the Guideline 2, but the effectiveness is limited.

SUM UP

1. Prof. ERDAL KURTOĞLU

In this complex disease affecting many organs, I think the most important thing is the diagnosis and identification of the patients. If the patient needs hemoperfusion, you should start as early as possible as the patient has some problems with this organ thread condition.

2. Dr. Liang Yu

In our study, we found that the time interval between symptoms onset and ICU admission are independently associated with death. The key point is to diagnose and treat the patients as early as possible.

3. Prof. Romina A. Danguilan

We have another option of therapy for demonstrative diseases, such as leptospirosis, acute liver infection, and COVID-19 virally infection. Most can cause severe lung hemorrhage, lung disease and sepsis. Hemoperfusion is an important and safe therapy. At last, an early diagnosis and early therapy are the most important and essential to save patients.

* The content above is based on the experts' clinical experience and opinions, and comprehensive consideration shall be needed in clinical practice.

References

1. Li Lanjuan, et al. Expert consensus: Application of artificial liver and blood purification system in the treatment of severe and critical pneumonia caused by COVID-19. Chinese Journal of Clinical Infectious Diseases, 2020, 13 (00): E003-E003.

2. National Health Commission & National Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) 2020.03.03

The webinar video is available on YouTube：

https://www.youtube.com/watch?v=ZzndPUHHQzM