Shifting the paradigm of long-term total parenteral nutrition: Lessons from renal dialysis

Parenteral nutrition (PN) stands analogous to renal dialysis in its role as replacement therapy to artificially substitute a failed organ system. Both therapies are lifesaving and allow patients to manage chronic conditions that would otherwise be fatal: just as dialysis circumvents compromised renal function to filter waste and excess fluid, PN bypasses a nonfunctional or absent gastrointestinal tract by delivering essential nutrients, protein, and fluid directly into the bloodstream. Through the lens of history, there have been many remarkable achievements of modern medicine. Renal dialysis is the pinnacle of organ replacement, which has transitioned from an emergency lifesaving procedure to a routine, gold-standard treatment for renal failure. Similarly, PN stands in its infancy on the cusp of a similar paradigm shift as a routine organ replacement therapy, which will improve patient survival and quality of life if we can address ongoing challenges, such as refining nutrient compositions to align more closely with physiological needs, reducing infection rates, mitigating liver dysfunction, and improving cost-efficiency.

The journey of renal dialysis begins in 1913 with the pioneering groundwork of John Jacob Abel. His “vividiffusion” invention was the first to demonstrate the principle of dialysis; however, it was not until the 1940s when Willem Kolff developed the first practical dialysis machine, known as the rotating drum kidney. This device was understandably rudimentary by today's standards, consisting of cellophane tubing wrapped around a drum submerged in a bath of dialysate, but it established the principle of removing waste products from the blood in acute kidney injury. This was succeeded by Fredrik Kiil's plate dialyzer, which became the standard for hemodialysis in the 1960s. The subsequent development of the hollow-fibre dialyzer by Belding Scribner and colleagues was another quantum leap. Scribner also introduced the arteriovenous shunt, which for the first time allowed for repeated access to the vascular system, making long-term dialysis possible.^{1, 2} The advent of biocompatible membrane technology, refinement of dialysate composition to more closely mimic human plasma, and the development of sophisticated machines that closely monitor and adjust the dialysis process in real-time further enhanced efficacy and patient safety. These advancements have made renal dialysis a gold standard of care in end-stage renal disease in the absence of transplantation. Rather than the prospect of death within weeks, dialysis offers millions of patients globally a 5-year survival rate of >50% and an improved quality of life.^{3, 4}

In the 1960s, the modern concept of intravenous feeding was formulated, roughly 50 years after the foundation of dialysis was laid. Stanley Dudrick and colleagues meticulously identified requirements and techniques to deliver a complete nutrition solution intravenously, which included proteins, carbohydrates, fats, electrolytes, vitamins, and trace elements. After demonstrating the feasibility of PN in beagles, their work culminated in the first successful human administration of PN to an infant with intestinal atresia in 1968.⁵ This pivotal moment in management of gastrointestinal failure led to subsequent refinements of PN solution composition, development of safer catheter placement techniques, and conception of protocols to broaden the applicability of PN. Present day, short-term use of PN is readily available in most tertiary hospitals particularly in the postoperative setting; however, transitioning to home (life-long) PN remains a restrictive endeavour but is feasible and offers good survival and valuable quality of life.⁶

Among its uses, PN is the single most important treatment for conditions in which a majority, or the entire, small bowel requires removal (subtotal enterectomy). Patients develop short bowel syndrome, which includes inadequate absorptive capacity of macronutrients and micronutrients, electrolytes, and fluids. This is incompatible with life and can only be managed by long-term PN.⁷ As a result, total enterectomy is viewed as the rate-limiting step in otherwise survivable conditions, such as acute mesenteric ischaemia or curative cytoreductive surgery (CRS) for peritoneal carcinomatosis. In fact, up to 47% of patients are not offered curative CRS specifically because of extensive small bowel involvement, despite studies that show patients with even aggressive pathology, such as pseudomyxoma peritonei or mesothelioma, can achieve a median survival of 50–60 months postoperatively.^{8, 9} As surgeons shy away from undertaking enterectomy, these patients undergo systemic treatment or comfort care while they inevitably progress toward bowel obstruction and enteric fistulae. Small bowel transplantation is yet to establish itself as a viable alternative in the steep face of high mortality rate and limited organ supply, plus a need for life-long immunosuppression.¹⁰ Future PN advancements to match the evolutionary strides made in renal dialysis could add enterectomy to a surgeon's repertoire and pave the way for more effective treatment in correctly selected patients with benign and malignant conditions, or as a bridge to transplantation as its outcomes also improve.

In its present iteration, PN carries potentially serious complications, such as catheter-related sepsis, metabolic derangements of glucose and micronutrients, and parenteral nutrition–associated liver disease. Long-term PN can also lead to loss of bone density, renal impairment due to nephrotoxic metabolite accumulation, and an increased risk of metabolic syndrome. Patients and caregivers must be meticulously trained in sterile techniques to mitigate the risk of central line infections and must also manage the complex infusion pumps and nutritional formulas. Further, the responsibility of managing lifesaving therapy can be psychologically taxing. Close monitoring for complications necessitates a well-funded and coordinated multidisciplinary team of physicians, specialist nurses, dietitians and others, which is challenging in the outpatient setting.⁶

As dialysis has seen a myriad of improvements over the last century, one would maintain optimism that similar progress will occur for PN to reduce complications and complexity and improve patient survival and, importantly, quality of life. This may be achieved by addressing the key challenges. Firstly, developing advanced lipid emulsions that mimic natural lipid profiles would mitigate liver complications and improve immune function. Secondly, pioneering catheter technology with antimicrobial surfaces or implementing more rigorous aseptic protocols would significantly decrease catheter-related infections. Thirdly, tailored PN regimens must be developed to individual metabolic demands and compressed to a short duration of hours per day for optimal patient quality of life while still preventing metabolic imbalances and nutrient toxicity.¹¹

Additionally, integrating regular monitoring and early intervention strategies for managing complications such as bone demineralization or renal dysfunction are crucial. The cost of long-term PN must also be rationalized by encouragement of market competition or government funding to support its financial utility as a long-term treatment.¹² Further, ongoing research into gut-trophic factors and intestinal transplantation could potentially reduce the duration of PN dependency. Such advancements will likely expand the definitive therapeutic indications for PN and avoid palliative measures in well-selected patients currently deemed terminal, as witnessed with renal dialysis for those with end-stage renal disease.

In an era of rapid advancements in precision medicine and the biomedical industry, the trajectory of ongoing PN improvements is on the horizon as it sits half a century behind the timeline of renal dialysis. Recognizing this parallel—a life-preserving organ replacement therapy delivered intravascularly—there is a need for a paradigm shift among clinicians in our perception, familiarity, and utilization of PN. By addressing the current controversies and challenges, long-term PN can become safer, more effective, and cheaper and improve survival and quality of life in well-selected patients.

The authors declare no conflict of interest.