3.3.4 Clinical benefits of PN

3.3.4.1 MORTALITY AND SURVIVAL

CRITICAL ILLNESS

• Results of a meta-analysis of seven studies involving 798 patients comparing PN with standard care (conventional oral diet and IV dextrose) by Braunschwieg and colleagues (2001) found that, in studies involving a high proportion of malnourished patients, standard care was associated with a significantly higher risk for mortality compared with PN (relative risk (RR) 3.0; 95% CI 10.9–8.56).³²² Although this study was conducted some years ago, it has informed current ASPEN and ESPEN guidelines on PN in the critical care setting, which recommend timely use of PN in the ICU if EN is contraindicated or not tolerated.^97,323 Given this recommendation, it is unlikely that future studies will be conducted to compare the use of PN versus no PN in critically ill patients who are malnourished or at high nutritional risk.
• Xian-li and colleagues (2004) conducted a randomised study to compare glutamine- supplemented TPN and standard TPN versus no TPN in 64 patients with serious acute pancreatitis receiving traditional therapy.³²⁴ Serum albumin concentrations were low at admission, suggesting poor nutritional status, but increased significantly after 2 weeks of standard or glutamine-supplemented TPN groups compared with no TPN (p < 0.05 for both comparisons). Furthermore, mortality was significantly higher in patients who did not receive TPN (43.5%) than in patients who received either glutamine-supplemented TPN (0.0%) or standard TPN (14.3%).
• Current ESPEN-aligned guidance supports the use of PN in acute pancreatitis when EN is not tolerated or contraindicated, particularly in patients at high nutritional risk due to the catabolic nature of the disease and its complications such as bowel obstruction, ileus, or mesenteric ischemia (Berlana, 2022).⁴

• A prospective multicentre cohort study by Compher and colleagues showed that greater protein and energy intake is associated with lower mortality and faster time to discharge alive in ICU patients who are at high risk for malnutrition.¹⁴⁸ A total of 2,853 mechanically ventilated patients with ≥4 days’ stay in the ICU and a subset of 1,605 patients with ≥12 days’ stay were included in the analysis. Most patients had been admitted to an ICU for medical reasons (65%) or emergency surgery (30%). TPN was used in 8.7% of patients and SPN in 13.8%. The results showed that every 10% increase in protein and energy intake relative to goal was associated with a significant decrease in odds of mortality of 6.6% and 7.1%, respectively, for high-risk patients in the ≥4-day group (p = 0.003 and p < 0.001) and by 10.1% and 11.6%, respectively, (p = 0.003 and p < 0.001) in the ≥12 day group.¹⁴⁸ Likewise, time to discharge alive was 5.1% and 4.5% shorter (p = 0.01 and p = 0.019) for each 10% increase in protein and energy intake, respectively, relative to goal in the ≥4 day group, and by 9.2% and 9.1% (both p = 0.002) in ≥12 day group.¹⁴⁸ These significant improvements in clinical outcomes occurred even though patients received only 62% and 59% of their goal energy and protein intake.
• A retrospective cohort study by Zusman and colleagues (2016) involving 5,053 critically ill patients who received enteral and/or parenteral feeding and were in the ICU for more than 96 hours showed that increasing protein intake (assessed as g per day and % of requirement, with a target of 1.3 g/kg) was linearly and independently associated with decreased 60-day mortality (HR 0.99, CI 0.98–0.99, p = 0.02).
• Nicolo and colleagues (2015) evaluated whether increasing protein delivery reduces mortality and time to discharge alive from the ICU.³²⁵ Data were analysed from the Canadian Improving Nutrition Practices in the Critically Ill International Nutrition Surveys 2013.³²⁵ The sample included 2,828 and 1,584 patients who remained in the ICU for ≥4 and ≥12 days, respectively (65% of patients were admitted to medical ICUs). Patients in the ≥4-day sample received an average of 60.5% and 64.1% of their prescribed protein and energy intake, respectively, while patients in the ≥12-day sample received 66.7% and 70.7%, respectively. The proportion of patients receiving PN or SPN was not reported. The results showed that higher protein intake was associated with reduced mortality in the ≥4-day sample (OR 0.63; 95% CI 0.47–0.84), adjusted model, and for the ≥12-day sample (OR 0.65; 95% CI 0.45–0.94), relative to patients achieving <80% of goal intake. Furthermore, in the ≥12-day sample, time to discharge alive was shorter for patients receiving ≥80% of prescribed protein (hazard ratio [HR] 1.25; 95% CI, 1.04–1.49).
• In a prospective observational cohort study by Allingstrup and colleagues (2012) involving 113 critically ill patients, higher protein provision was associated with improved survival time.¹⁴⁴ The results were confirmed in a Cox regression analysis, which showed that increased protein provision was associated with a significantly lower hazard ratio for death (risk of death vs time was decreased by 2% for each g of protein and amino acids provided; unadjusted HR 0.98; 95% CI 0.96–0.99; p = 0.01). The results remained significant after adjusting for baseline patient characteristics. However, provision of energy, resting energy expenditure, and energy and nitrogen balances were not related to the risk of death in these patients.
• Alberda and colleagues (2009) conducted an international, multicentre study (167 ICUs from 21 countries) to investigate how the amount of protein and energy administered affected clinical outcomes.⁹⁸ They followed 2,772 mechanically ventilated patients to determine 60 day mortality and number of ventilator-free days; 8.0% or patients received TPN and 17.6% received SPN (ETF + PN). Patients received an average of 1,034 kcal and 47 g of protein per day. Regression analysis showed that an increase of 1,000 kcal per day reduced 60-day mortality [OR 0.76; 95% CI 0.61–0.95; p = 0.014] and increased the number of ventilator-free days (OR 3.5; 95% CI 1.2–5.9; p = 0.003) for patients with BMI <25 or ≥35 kg/m². Likewise, an additional 30 g protein per day reduced 60-day mortality (OR 0.84; 95% CI 0.74–0.96; p = 0.008) for patients with a BMI <25 or ≥35. The authors suggest that increasing nutrient provision in the early phase of critical illness to minimise protein–energy deficit may improve clinical outcomes, particularly in patients with a low or high BMI.
• These findings are further supported by a systematic review showing that supplemental PN significantly improved protein and energy delivery in critically ill patients, reduced nosocomial infections (RR = 0.733, p = 0.032), and lowered ICU mortality (RR = 0.569, p = 0.030), without increasing adverse outcomes.¹²²

• Weijs and colleagues (2014) reported out a post-hoc analysis of prospectively collected observational data from a mixed medical/surgical ICU in the Netherlands.³²⁶ Data were from 843 critically ill patients who received prolonged mechanical ventilation (>72 hours). Protein was provided with a target of 1.2–1.5 g/kg pre-admission body weight; 1% of patients received TPN and 26% received SPN (ETF + PN). Higher protein intake was associated with significantly lower mortality in non-septic, non-overfed patients (n = 419): 36.8%, 35%, 26.5%, and 19.1% in patients with protein in takes of <0.8, 0.8–<1.0, 1.0–<1.2, and ≥1.2 g/kg, respectively (p = 0.033). Hospital mortality was 34.5% for patients with day 4 protein intake <1.2 g/kg compared with 19.1% for patients with protein intake ≥1.2 g/kg (p = 0.015).
• These findings are supported by a review by Hellerman and Singer (2020), which emphasises that achieving adequate protein intake early in critical illness—often requiring parenteral nutrition—is associated with improved outcomes, including reduced mortality and shorter time to discharge in mechanically ventilated ICU patients.²

• In a prospective RCT by Fan and colleagues in patients with undergoing surgery for severe traumatic brain injury, the mortality rate was significantly lower in patients receiving SPN (ETF + PN) than in patients receiving either ETF or PN alone (χ2 = 7.50, 16.37; p < 0.05, p < 0.01).²⁷⁶

INTESTINAL FAILURE

• Guidelines highlight that PN is a life-sustaining therapy for patients with reduced GI function who are unable to absorb sufficient macronutrients and/or water and electrolytes to meet their nutritional needs and therefore does not require evaluation of efficacy in RCTs.³² Furthermore, the ability of PN to preserve QOL and promote rehabilitation supports its use in the home setting (HPN).³²
• Recent trial data shows that long-term HPN regimens are safe, well-tolerated, and improve fatty acid balance in patients with chronic intestinal failure, without adversely affecting liver function. ³²⁷

• Pironi and colleagues (2012) conducted a benchmarking exercise to compare the literature on HPN against the results of a prospective European survey that evaluated the appropriateness of the current indications for HPN.⁴⁷ Analysis of the published data showed that HPN is associated with a high probability of survival, as evidenced by a decreasing annual mortality rate over time with HPN (>5% during the first 3 years ~5% for years 3–5; <5% for years 5–10). Patients with CD had the best outcome, with a mean survival rate of 88% at 10 years. Furthermore, the best survival outcomes were observed in patients <40–45 years. This study also found that most deaths in adults during HPN were due to the underlying disease, not as a complication of HPN.
• Dibb and colleagues investigated long-term survival in adults who received HPN at a UK national referral centre for IF over a 33-year period.²⁵⁶ Data from 545 patients who received HPN for more than 3 months between 1978 and 2011 was analysed (2,330 patient-years’ HPN). Overall survival rate for patients without malignancy at the time of IF was 93%, 71%, 59%, and 28% at 1, 5, 10, and 20 years, respectively. Multivariate analysis showed that overall survival was better in patients with CD, mesenteric ischaemia, and chronic intestinal pseudo-obstruction than in those with scleroderma or radiation enteritis.

• Colomb and colleagues (2007) reported data on the long-term outcomes of 302 children who received HPN at a single centre in France in 1980–1999.³²⁸ Median age at start of HPN was 1.5 years, and median duration of HPN was 1.3 years. By the end of the study, 54% of children had been weaned from HPN and 26% were still receiving HPN. The survival rate at 2, 5, 10, and 15 years were 97%, 89%, 81%, and 72%, respectively, with outcome and survival mainly determined by the underlying disease. The authors concluded that nearly all children with primary digestive disease survive if they are referred early to a specialised centre for nutritional support.
• More recently, Nader and colleagues (2013) reviewed data from 251 children with IF who were discharged on HPN from a single centre during 2000–2013³²⁹ (mean age at HPN initiation, 0.7 ± 0.3 years; mean duration of HPN, 1.9 ± 0.4 years). At the end of the study period, 52% of patients had been weaned off PN, after a mean of 1.9 years, and 34% of children were still receiving HPN. Rate of catheter-related complications was low (mean 1.7 ± 0.5 per 1,000 days of HPN) and decreased from 2012. Twenty-four children died while receiving HPN (10%), the majority from the underlying disease.
• These findings are supported by international expert consensus, which states that long-term PN has significantly improved prognosis in children with primary intestinal failure, especially those with short bowel syndrome and mucosal diseases .³¹

CANCER

• ESPEN guidelines highlight that HPN may be a superior to surgical intervention in terms of survival and long-term nutrition autonomy for some patients with chronic radiation enteritis (CRE) based on the results of two studies.¹⁶⁸ The first was a retrospective study by Gavazzi and colleagues (2006) involving 30 patients with mechanical bowel obstruction due to CRE who were divided into two groups based on their initial treatment (HPN or surgery).¹⁸⁶ Overall 5 year survival was significantly longer for patients in the HPN group (p = 0.0231). Furthermore, all patients in the HPN group achieved nutritional autonomy, compared with 58.8% of patients in the surgery group (p = 0.01). The second study, by Kalaisselvan and colleagues (2014), involved analysis of data on nutritional and survival outcomes in 23 patients with CRE referred to a national IF unit over 1998–2011 (1,994 patient-years).¹⁸⁷ Most patients with IF secondary to CRE required long-term HPN, and surgical intervention was needed infrequently. The 10-year survival of the cohort was 48.2%.
• A recent systematic review confirmed that HPN remains a critical intervention in malnourished oncology patients with gastrointestinal dysfunction, including bowel obstruction, where enteral options are not feasible. Across 19 studies, HPN was associated with improvements in weight, functional status, and quality of life, and one prospective trial showed significantly greater weight gain in patients receiving higher protein PN (1.15 g/kg/day vs. 0.77 g/kg/day). ³³⁰

• ESPEN guidelines on nutrition in cancer patients highlight that for patients expected to survive for several months, artificial nutrition may improve survival in those who are unable to meet their nutritional needs through the oral route.¹⁶⁸ Two studies are cited in support of this statement. Bozzetti and colleagues (2014) prospectively studied the associated between patient or clinical characteristics and survival with HPN in 414 patients with incurable cancer.¹⁸⁶ Mean and median survival were 4.7 and 3.0 months, respectively; and significantly prognostic variables were Karnofsky PS, tumour spread, and Glasgow Prognostic Score. Importantly, 50% of patients on HPN survived longer than typically observed for historic controls (i.e., ≤2 months for hospital patients without PN support and <2–3 weeks for patients followed at home), with about 25% of patients surviving for ≥6 months. This suggests that HPN may confer a survival benefit for some patients with incurable cancer. The second study was a retrospective study by Fan and colleagues (2007) to identify long-term survivors (alive >1 year after start of HPN); 115 patients with malignant GI tract obstruction were identified who had received HPN as palliative care.¹⁹⁰ Median time from start of PN to death was 6.5 months; 11 patients survived ≥1 year and 2 patients were still alive at almost 4 years.
• Soo and colleagues (2008) conducted a cohort study in 38 patients with advanced cancer enrolled in a HPN program in Canada, to identify patient-related variables associated with survival.³³¹ Higher Karnofsky PS (>50) at the start of HPN was associated with longer median survival (6 months, vs 3 months in patients with Karnofsky PS <50; p = 0.001).
• In the randomised prospective study conducted by Lundholm and colleagues (2004) to investigate the impact of specialised nutrition-focused care (including PN) in 309 cancer patients with progressive cachexia (primarily due to GI tumours), patients receiving PN had longer survival than patients who did not receive nutrition report (p < 0.01; survival duration not reported) compared with control patients who did not receive nutrition support.²⁹⁷
• Hoda and colleagues (2005) carried out a retrospective analysis of data from 52 adults with incurable cancer to determine whether HPN extends survival. Median time from start of HPN to death was 5 months (range 1–154 months); 16 patients survived for at ≥1 year, suggesting that HPN may be associated with long-term survival in selected patients with incurable cancer.³³²
• Guerra and colleagues (2015) evaluated the impact of PN on survival in 55 patients undergoing active treatment for cancer-related intestinal occlusion, 85% of whom were malnourished.³³³ The survival rate was higher in patients who received HPN after hospital discharge than in those who remained in hospital (log-rank 7.090; p = 0.008). Furthermore, survival was prolonged in patients who started chemotherapy during or after initiation of PN (log-rank 17.316; p < 0.001). Importantly, 51% of patients were able to receive further chemotherapy after starting PN because their PS (European Cooperative Oncology Group; ECOG) had improved.
• Brard and colleagues evaluated the use of TPN in a historical cohort of 55 patients with terminal intestinal obstruction related to ovarian cancer. Patients receiving TPN survived a median of 72 days, compared with 41 days if TPN was not administered (p = 0.01),³³⁴ and the mortality rate ratio for TPN versus no TPN was 0.59 (95% CI 0.35–1.00). Sixty-four percent of women receiving TPN were concurrently receiving chemotherapy, compared with 24% of those not receiving TPN, which may reflect patient and physician preference for concurrent TPN and chemotherapy. Stratified analysis showed that patients who received both chemotherapy and TPN after terminal intestinal obstruction had a median survival of 74 days, compared with 42 days for those not receiving concurrent TPN (p = 0.09); the mortality rate ratio was 0.54 (95% CI 0.23–1.30).
• A recent narrative review noted that PN improves quality of life and survival in cancer patients when oral or enteral nutrition is not feasible, particularly in cases of advanced disease and malnutrition.¹⁸⁰
• A prospective study of 130 patients with advanced cancer receiving HPN found that overall median survival was 123 days and was similar between patients using ready-to-use multichamber bags and those receiving individualised PN. Importantly, survival was significantly longer in patients who were able to start or continue chemotherapy after HPN initiation. This suggests that HPN can help maintain nutritional and performance status in advanced cancer patients, thereby enabling continued oncologic treatment, which was associated with improved survival in this study. ³⁷
• Additional expert recommendations suggest that HPN may be appropriate in advanced cancer only when expected survival exceeds 2 months and patient-centred goals justify the intervention. ³³⁵

INFLAMMATORY BOWEL DISEASE

• Evans and colleagues (2003) reviewed hospital pharmacy data on all patients with IBD who received HPN between 1996 and 2000,³³⁶ and conducted telephone interviews to assess QOL. The 15 patients included in the study received an average of 75 days’ PN (range 7–240). HPN was deemed successful in 80% of patients such that 53% of patients were able to receive planned definitive surgery and 27% did not require surgery because their condition resolved while on HPN. All patients preferred HPN to further hospitalisation and reported their QOL at home to be good or excellent.

KIDNEY DISEASE

• In the multicentre open-label Phase 4 RCT conducted by the German IDPN Trial group, IDPN, administered three times weekly for 16 weeks, resulted in a statistically significant and clinically relevant increase (≥15%) in mean serum prealbumin (p < 0.05), a surrogate marker for outcome and survival in HD patients with malnutrition,³³⁷ compared with nutritional counselling.³¹⁰
• Analysis of data from a 2-year prospective randomised study comparing IDPN plus ONS with ONS alone in malnourished patients on HD showed that while IDPN did not improve overall 2-year mortality, an increase in prealbumin >30 mg/L within 3 months independently predicted a 54% decrease in 2-year mortality (OR 0.46; 95% CI 0.27–0.79), reduced hospitalisations, and improved general wellbeing (measured by the Karnofsky PS) (p values not reported).³³⁷