**2. History of parenteral nutrition development**

The complexity of PN technique proved challenging and successful long-term administration was not performed until 1968, even though PN is now considered an essential clinical strategy in modern medicine [3]. Interestingly, NASA accelerated the field by attempting to formulate standardized elemental nutrition solutions during the Mercury space program. For almost 400 years prior, clinicians attempted to administer numerous solutions intravenously, including salt water, milk, and wine, with limited success [4]. The first successful use of PN in humans was performed by *Dudrick and Wilmore* when they intravenously supported an infant with PN for 6 weeks [3]. This development led to the rapid use of PN in clinical settings. Early on, PN was administered prophylactically to many patients in pre- and postsurgical settings regardless of their nutrition status. In today's practice, patients are first assessed for whether the risks outweigh the benefits of either short-term or long-term PN feeding. The decision to use PN has become more selective because long-term PN confers certain clinical risks related to vascular access, inflammatory bowel disease, catheter site infections, improper brain development (in neonatal settings), and other metabolic complications such as hepatic steatosis and cholestasis related to the continuous hypertonic glucose solution entering circulation compared with intermittent enteral feeding. When PN is used in otherwise healthy and well-nourished patients, these individuals are exposed to these risks without room for significant nutritional benefit [5–8].

Several clinical trials supported the shift to reserving PN for those with GI failure or malnutrition. In one trial, 400 general surgery patients were preoperatively randomized to receive either PN alongside *ad lib* oral feeding or *ad lib* oral intake alone [9]. The results demonstrated that PN elevated the risk of major infections and did not reduce non-infectious complications between treatment groups. However, further analysis demonstrated that subjects with existing malnutrition in the cohort did benefit from PN by exhibiting improved wound healing compared with the control group [9]. These results showed that PN provides the greatest benefit in malnourished patients, and that nutritionally replete patients could be exposed to harm from PN complications with minimal benefit. Clinicians are still faced with challenges, since definitions of nutrient status and malnutrition vary across the life span, clinical settings, and between disease states, making exact categorization of patient nutritional status and risk-benefit balance difficult [10]. With these challenges in mind, PN is generally targeted to surgery patients with existing malnutrition or individuals who are not expected to feed enterally for 7–10 days, since loss of lean muscle begins within 2 weeks following lack of enteral intake.

In addition to general surgery settings, another common setting of nutritional deficiency occurs in patients with hypermetabolic states following acute infection or those with traumatic injuries where rapid proliferation of immune and organ cells is required [1]. The average human typically maintains 1200 kcals in hepatic glycogen storage, before lean muscle mass and peripheral fat are utilized to support

#### **Figure 1.**

*The rise in parenteral nutrition biomedical research publications determined by pubmed keywords used between 1940 and 2020.*

energy requirements [11]. Under acute infectious or injurious challenge, enhanced immune activation, increased oxygen consumption, and elevated muscle catabolism rapidly results in negative nitrogen balances. Even patients with no existing nutritional deficiencies may require PN when their energy needs are increased beyond their stored nutrient capacity. These settings also present challenges to the clinician, as it is established that a greater degree of injury leads to a higher risk of malnutrition [12, 13].

It is now accepted that enteral nutrition with a functional GI tract is the preferred route of nutrition in stable patients who can feed or tolerate feeding of either normal diet or standardized formula. Enteral nutrition is not without challenges, especially in patients where obtaining enteral access is difficult and the intestine requires time to adapt to calories. Specific to the latter case, enteral feeding also increases the risk of diarrhea, gut distention and upset. When tolerated, enteral nutrition leads to better clinical outcomes, including decreased risk of intraabdominal abscess and respiratory infection, total length of stay, medical costs, and mortality [5, 9, 13–19]. PN remains essential for patients who cannot feed enterally, but these risks must always be considered. This chapter will discuss how PN impacts the gut immune system and microbiome, gut-liver axis, gut-brain axis, and future opportunities in PN research (**Figure 1**).
