Rationale and Need for Simpler and Effective Miniaturized Bedside Ultrafiltration Devices

In several clinical situations, the elimination of the excess fluid which accumulates in various clinical conditions (heart failure, kidney failure, edematogenic syndromes) is inadequate or insufficient. In these situations, water overload causes increased hospitalization and mortality and is associated with major clinical consequences as acute kidney injury [1], prolonged need of mechanical respiration [2], impaired wound healing [3], prolonged hospitalization [4], and death [5]. In most of these cases, physicians use diuretics to increase urine volume. Nevertheless, in a significant percentage of patients, the pharmacological approach does not work effectively on the fluid overload and this leads to an unfavorable clinical and social outcome. Extracorporeal ultrafiltration is a well-established technique; however, the equipment is bulky and requires highly specialized environments. The creation of a miniaturized, simple, and portable device for extracorporeal ultrafiltration with innovative characteristics could promote an incredible step forward in the management of fluid overload; the ultrafiltration technique could be performed in any environment both at hospital and home, facilitating the possible self-administration of therapy. Artificial diuresis through such a device responds to a rationale articulated on several fronts.

Water overload is a risk factor for cardiovascular, lung, and kidney complications; it also leads to an increase in mortality in critical patients in the intensive care unit (ICU), for heart failure patients, and patients affected with kidney dysfunction [3, 6, 7]. The water balance in the organism is maintained under different pathological conditions as follows:

Normal conditions: physiological diuresis (normal renal function).

Pathological conditions: forced diuresis (diuretic drugs).

Advanced pathological conditions: artificial diuresis (extracorporeal ultrafiltration).

There are algorithms which helps in the decision of starting mechanical ultrafiltration when physiological and/or forced diuresis is no longer sufficient [8, 9]. Water overload is a condition in which it is essential to restore the volume of extracellular fluid and achieve a negative fluid balance. This process tries to simulate the function of the native kidneys. There is therefore a theoretical and scientific rationale to develop a simple and easy-to-apply method to achieve a normal hydration state.

Edema-generating pathologies are very common and determine hydro-saline retention both in hospitalized patients (acute heart failure, decompensated nephrotic syndrome, liver cirrhosis in the ascitic phase, acute and chronic kidney failure) and in patients followed at home (chronic heart failure, oncological pathologies, nephrotic syndrome, liver failure). In all these patients, diuretic therapy represents the standard treatment; however, it does not always reach the therapeutic target and when it happens it does not last for a long time (frequent hospitalizations and re-hospitalizations). If the pharmacological therapy does not work, the treatment of choice is extracorporeal ultrafiltration. This is considered a “rescue therapy.” Recently, extracorporeal ultrafiltration has been suggested to be an “elective therapy”; this should be proposed in the early stages of the disease in order to prevent the development of complication that may require hospitalization. In a recent analysis of the leading causes that lead clinicians to prescribe extracorporeal therapy in critically ill patients (as in COVID-19 patients), the main indication is the need to restore the normal hydration status [5]. In both adults and pediatrics, there is evidence that even mild hyperhydration represents a risk factor for mortality [5].

The existing technology is based on the experiences from the 1970s and on well-known physical concepts (through a membrane separation process, plasma water is produced from blood). However, there has not been any evolution on techniques which have however a greater safety. The equipment for extracorporeal therapy is bulky and their number is limited; this prevents their use in clinical practice (as recently reported by the American press in the course of a SARS-Cov-2 pandemic). Furthermore, these techniques require the cannulation of central veins and can cause hemodynamic instability with renal hypoperfusion leading to increase in serum creatinine. Nevertheless, there is evidence of a therapeutic efficacy of ultrafiltration in patients with heart failure as recently reported in the literature [10, 11]. There are benefits on cardiac and kidney function and an improvement on patients’ well-being and quality of life is reported. It is clear that these kinds of treatment are very useful but the technology, the logistics, and practical organization need to be redefined.

It is clear that we face a clinical and technological need that can be satisfied by a new technology that needs the development of the following points:

a. Realization of a simple, compact, safe, portable, and miniaturized hardware

b. A technology that can be managed through a peripheral vascular access

c. A technology that provides a wireless and battery powered device

d. Management of therapy in complete safety with easy replacement of the disposable component

e. A technology that uses a simple and easy software

f. Management of technical complication through simplified troubleshooting processes

g. A wider range of application and the possibility of using it as a rescue therapy

h. An extend application of this technique as an “elective therapy”

i. A widespread hospital application which is not limited to the intensive care department

j. An out-of-hospital application with the possibility of home therapy

k. A technology that allows the patient to independently manage the therapy

l. A technology that does not worsen kidney function or electrolytes

This technology could be a breakthrough in the management of acute and chronic water overload because today extracorporeal ultrafiltration is applied only in a late phase of the disease.

In the healthcare system, we have witnessed an evolution of technologies in recent years like sensors for blood glucose, micro injectors, pacemakers, and neuromuscular stimulators. Technological progress is directed toward nanotechnologies, mechatronics, and microfluidics. This evolutionary progress has allowed the fusion of different scientific areas. Ultrafiltration techniques have remained anchored to past schemes and there is a need for a change in technology and clinical mentality. A device is urgently needed that allows the application of continuous artificial diuresis for 24 h or less which is slow, progressive, adjustable, and safe. It has to be available for home use representing the logical and innovative evolution of technologies and devices used in the past.

Health systems suffer from a financial burden of chronic diseases, in particular heart failure, kidney failure, and oncological pathologies. Patients affected by these chronic pathologies are not self-sufficient and often require hospitalization. This leads to very high healthcare costs. De-hospitalization and direct participation of the patient in his own therapy achieving autonomy are the goal to pursue with the possibility for the physicians to monitor the patients at home from the hospital. Within hospitals, there is a need for small equipment which can be used in medical departments. The opportunity to obtain a safe artificial diuresis at the patient’s bed outside the ICUs represents the opportunity to reorganize services within hospitals.

The management of chronicity represents a challenge for modern society and for the healthcare systems of the most advanced countries and is gradually becoming an actual concern for the less developed countries. There is a need for sustainable and eco-compatible technologies that use biodegradable materials, low consumption, and low-cost equipment. The key to achieve this goal is the development of miniaturized, portable technologies able to respond to a clinical need.

The principle behind any development in the biomedical field must be patient safety and a proven real benefit for the patient. We can look at this from the patient perspective, in which the removal of excess water leads to a clinical benefit and less hospital admission, and from a general prospective as a commitment toward all the pathologies in which water overload is a serious issue that needs to be approached from a different angle; this could lead to an improvement on the quality of life for the patient and a reduction in morbidity, mortality, and healthcare costs. The multidimensional rationale of this project leads us to think of different possible clinical scenarios in which the smart artificial diuresis could be applied, thanks to the proposed miniaturized device:

1. Acute heart failure: slow and progressive removal of fluid adjustable at variable rate similar to physiological diuresis

2. Critical condition in the ICU: management of the fluid balance in case of oliguria or excessive need for infusion, regardless of dialysis therapy

3. Recent kidney transplantation: management of the fluid balance in case of delayed allograft function

4. Patients on ECMO: management of fluid balance during or after extracorporeal oxygenation

5. Decompensated nephrotic syndrome and anasarcatic state: management of water overload

6. Decompensated liver cirrhosis: management of fluid overload

7. Chronic heart failure: management of water overload in the initial stages of decompensation (rescue therapy) or management of the prevention of re-hospitalization with periodic treatments (elective therapy)

8. Patient with initial kidney failure and need of water rebalance

9. Hypoalbuminemia and generalized edema states: reduction of fluid overload

10. Pediatric patients with the need to optimize the water balance: the miniaturized nature of the device allows it to be used in patients of reduced size up to the neonatal level

11. Treatment of water overload in the interdialytic period

12. Treatment of water overload in patients on peritoneal dialysis with insufficient transperitoneal fluid removal

13. Treatment in protected environment like retirement homes

14. Home management of chronic water overload

Possible alternatives to using the device with adequate modification to the circuit and filter element are as follows:

1. Pediatric treatments of various kinds

2. Plasma filtration or plasma separation

3. Plasma filtration adsorption

4. Hemoperfusion/hemoadsorption

The simplicity of the technique and of the device opens up new possible indications in different clinical scenarios [12, 13].

C. Ronco received honoraria for advisory boards, consultation, or speaker bureau in the last 3 years from the following companies: Asahi Medical, Astra Zeneca, Baxter, Biomerieux, Aferetica, Cytosorbents, FMC, GE, Medica, Jargon, B. Braun, Toray, and ESTOR. A. Brendolan received honoraria for consultation from Medica. L. Sgarabotto has no COI to declare.

No funding sources were present for this article.

Study concept and design: C.R. and A.B. Drafting of manuscript and critical revision of manuscript for important intellectual content: C.R. and L.S.