Effect of Early versus Delayed Parenteral Nutrition on the Health Outcomes of Critically Ill Adults: A Systematic Review

Nutritional support is considered an integral element in the treatment of seriously ill patients admitted to the ICU. Optimum nutrition levels are essential to maintain competent immune function, support anabolism, reduce the metabolic response to stress, decrease oxidative cell damage, and ultimately to improve critically ill patients’ health status [1]. Nutrients supplied for therapeutic reasons, whether orally, enterally, or parenterally are specified as specialised nutrition support (SNS). PN is used for patients who cannot be fed an appropriately oral diet or if the digestive tract is not functioning or inaccessible [2]. Enteral nutrition alone provides only 45% to 60% of energy due to difficulties with its provision rate. A supplemental PN strategy aims to address EN’s energy gap to meet 100% of the daily energy demands. However, reports on its impact on clinical outcomes have been inconsistent in reported trials [3, 4]. It has been recommended that energy provision be increased from 70% to 100% of estimated needs for three to seven days of ICU post-admission [4, 5].

Timely initiation of optimum nutritional support is vital to limit the catabolic process and reduce adverse outcomes such as prolonged mechanical ventilation, more prolonged ICU stays, and increased mortality risk [6].

Nutritional support through the parenteral route has traditionally been associated with more significant risks and complications such as infection compared to the enteral route. However, recent developments in the supply, formulation, and monitoring of PN suggest that more up to date comparison studies and analysis of these nutritional support routes, especially in the early phase of the disease, are now required [7]. Furthermore, the use and optimal timing for PN initiation remain less well defined, also European and North American guidelines differ significantly [8].

The Society of Critical Care Medicine (SCCM) and the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines recommend that patients with severe malnutrition be given PN as soon as possible after admission to an ICU when EN is not feasible. However, in patients at low nutrition risk (NRS-2002 ≤ 3 or NUTRIC score ≤ 5), exclusive PN is withheld over the first seven days following ICU admission [5].

Contrary wise, the 2019 European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines stated that clinical nutrition should be considered for any patient staying in an ICU for more than 48 hours, and PN should be initiated within three to seven days, post-admission, when EN is contraindicated [9]. According to the Canadian clinical practice guidelines (2015), PN should not be started simultaneously with enteral nutrition and should not be used routinely in patients with an intact gastrointestinal tract. However, few data relating to patients who do not tolerate adequate enteral nutrition recommend the optimum time to initiate parenteral nutrition [10]. Moreover, there are no Indian guidelines and protocols available as to when parenteral feeding should be initiated.

Several reported studies showed the superiority of enteral nutrition over parenteral nutrition in some aspects and vice versa [11, 12, 13]. However, very few systematic reviews were explicitly conducted to explore the impact of early versus late parenteral nutrition and parenteral nutrition versus supplementary parenteral nutrition in adults. To date, no meta-analysis has been published on this issue. Also, guidelines and research results contradict parenteral nutrition, which creates more confusion regarding parenteral nutrition optimally.

This review aims to evaluate and summarise the findings of all relevant studies that identified the effect of early versus delayed parenteral nutrition, early PN versus early supplemental PN, and early parenteral nutrition versus standard care in critically ill adults.

A total of 2088 potentially relevant articles were identified via searching Embase (N=782), PubMed (N=711), Ovid Search (N=448), Clinical Key (N=147). Additional records were included through other sources (n=1). After removing duplicates, 1083 articles were screened based on their titles and abstracts. Twenty-three full-text articles were reviewed based on the inclusion and exclusion criteria of the review. Of these, eighteen articles were excluded as they did not meet the eligibility criteria. One retracted trial was identified, one appraised article, two paediatric trials, one ongoing trial, five were sub-study or secondary analysis of a major clinical trial (EPaNIC study), and eight studies had an unmatched intervention. Five RCTs were finally identified for inclusion in this systematic review (Figure 1).

The review included five trials that enrolled 6,277 participants, ranging from 45 to 4640 participants. The mean age of the participants ranged from 41.6 and 68.6 years in all included trials. Three of the five reported studies [15,18,19] related to critically ill medical and surgical adult patients. One of the studies [17] had enrolled participants with traumatic brain injury, and one trial [16] had patients with severe acute pancreatitis. Of the total clinical trials included, one trial [15] compared EPN and LPN, one trial compared early TPN and standard care [18], one trial [19] compared supplemental PN with standard care, and two trials [16, 17] compared TPN and supplemental PN. Basic characteristics and clinical outcomes of the included studies are given in Table 1 and 2, respectively.

The review was divided into three objectives to understand better the initiation timings of the supplemental parenteral nutrition. The primary outcomes were mortality, quality of life, length of ICU, and hospital stay. The secondary outcomes were complications such as infection, organ failure, and metabolic and gastrointestinal complications.

Caesar M. (2011) [15] reported similarities in early (within 48 hours) and late parenteral nutrition group (after seven days) mortality rates, but also a 6.3% rise in the likelihood of earlier ICU and hospital alive discharges in the late parenteral nutrition group. In support, Shah S. (2019) [21] also reported no significant differences in mortality rates between early (within seven days) and late (after seven days) PN groups. However, it was also evident in other studies that early PN reduces patients’ hospital stay [18, 21]. On comparing early PN with the supplemental PN group, the RCTs evidenced higher mortality rates in the early PN group than the supplemental PN group [16,17]. However, a large multicentre observational study suggested that the provision of protein and calories to critically ill patients could improve with supplemental parenteral nutrition; no clinical benefit was identified [22].

Moreover, clinical trials involving standard care versus supplementary PN showed no significant variations in mortality rates in both groups [18,19]. Thus, patients in the early or late parenteral nutrition group, supplementary PN group, and the standard treatment group were assumed to have no significant differences in mortality rates. However, the standard treatment in both trials was different [18,19]. Doig G (2013) included nearly 40% of patients who eventually received delayed enteral nutrition; some patients received delayed enteral or parenteral nutrition. Some remained unfed during their ICU stay [18]. However, Ridley E. (2018) [19] described the standard treatment as offering PN when EN was inadequate. At the same time, the intervention group provided a supplemental PN approach administered for up to seven days, and the total average energy and protein requirement were different in both the standard treatment group and the supplemental PN group, i.e., 2092 (392) kcal, and 103 (21) g respectively.

A shorter ICU stay and the probability of earlier discharge of the patients from hospital care was observed in the late initiation PN group, when treatment was delayed for more than eight days after ICU admission, compared to early initiation of treatment. Patients in the EPN group remained in the ICU for three days more than the LPN group patients [15]. In contrast, Shah S. (2019) [21] reported a significantly shorter hospital stay in the EPN group (within seven days) than the LPN group (after seven days) of admission.

However, when PN was supplemented with EN, an ICU stay was significantly prolonged in the PN group compared to the SPN group [16,17]. It has been found that there was no difference between the functional status, as assessed by a six-minute walk, and in daily living activities, of EPN and LPN group at the time of hospital discharge [15]. In contrast, it has been reported that early parenteral nutrition was found to be protective against both muscle wasting and fat loss, with significant early benefits appearing to persist over the patient’s entire ICU stay compared to standard treatment [18]. Correspondingly, a study found that patients who had undergone PN post-surgically for gastric cancer can substantially improve the quality of life, nutritional and psychological status, and patients’ immune functions [23].

In terms of infection, it was found that fewer patients acquired new infections in their respiratory tracts, blood circulation, or wounds. However, there were a more pronounced acute inflammatory response and hyperbilirubinemia in the LPN group than in the early initiation group. Cases with a rise in aminotransferase levels were similar in both the LPN and EPN group [15]. After doing sub-analysis of the study done by Casaer M. (2011) [15], the EPaNIC trial of early PN versus late PN found that tolerating significant caloric deficit by restricting PN until day eight of critical illness increased plasma bilirubin but decreased the incidence of biliary sludge and decreased gamma-glutamyl transferase, alkaline phosphatase and alanine aminotransferase (GGT, ALP) [24]. A secondary analysis of the EPaNIC trial showed that postponing any PN use to supplement insufficient EN beyond one week in the ICU significantly reduced the risk of acquiring an invasive fungal infection in the ICU by 32% [25]. Similarly, it has been observed that feeding patients to cover an individualised measured energy target with supplemental PN from day four was associated with improved immunity, less systematic inflammation, and less muscle mass loss. A lower intracranial infection and pyemia were also found in the supplemental PN group than the PN group [17].

When the TPN and supplemental parenteral nutrition were compared, both the groups had a higher number of multiple organ dysfunction syndromes, increased cases of gastrointestinal bleeding. However, cases of abdominal distention, regurgitation, or aspiration were significantly lower than the EN group [16]. In the same way, no significant difference was observed in the rates of new infections, incidences of organ failures, and cases having gastric residual volume more than 300 ml, abdominal distension, and vomiting between the standard care groups and early TPN [18,19]. These discrepancies between the researches regarding the health outcomes of the patients receiving parenteral nutrition could be due to the heterogeneity in the study sample, i.e. patients with medical illness, surgical procedures, neuro-trauma [17], and severe acute pancreatitis [16]. So, the energy requirement of the patients varies accordingly. This is in agreement with a systematic review that emphasised that differences between the groups for nutritional delivery and energy requirements cannot be ignored as a possible factor for nosocomial infection. However, it is not known how, irrespective of the composition of nutritional support, an increased number of calories may affect nosocomial infection [26].

It is said that though PN is more straightforward to deliver than EN, its metabolic consequences are more difficult to manage [27]. Metabolic PN status such as blood glucose, normal urea, creatinine, and electrolytes such as chloride, bicarbonate, phosphate, plasma triglycerides, magnesium, and signs of infection should be routinely assessed.

A recent report on current practice and standards in the United Kingdom stated that, while delivering PN, “good practices” were followed in only 19% of the cases. Furthermore, there was a reported lack of supervision and assessment in 54% of managed patients. Also, PN-related metabolic complications occurred in 40% of cases, out of which 49% of these complications could have been prevented if necessary steps had been taken [28].

The monitoring issue is usually not discussed in nutrition recommendations, even though it is crucial in achieving success with any therapy [29]. For critically ill patients, using a straightforward approach means opposing one nutritional approach over others is no more a fair solution. An early aggressive feeding strategy, delivering full estimated energy targets from day one, was inappropriate regardless of the route [26].

This review found that patients on supplemental PN had shorter ICU stays and lower mortality rates than those on PN alone; however, these results should be interpreted carefully as included studies have different patients’ conditions, varying nutritional support composition and intervention timings. Hospitals should have fixed feeding protocols regarding early over delayed parenteral nutrition and early PN over standard treatment. This would ensure better feeding and nutritional status among hospitalised patients.