May 2018 E-Journal Club

Greetings,

Our journal club article for May was a departure from our usual choices, because the article was several years old. Although we missed reviewing this article at the time of its publication, our group thought it would be helpful to take a closer look at the methods and results of this study. There is such a limited body of literature regarding refeeding syndrome, and very limited data about refeeding that is from controlled investigations.

May Citation:

Doig GS, Simpson F, Heighes PT, et al. Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial. Lancet Respir Med. 2015 Dec;3(12):943-952.

Summary: 

This was multicenter, randomized, single-blind (with concealed allocation) study of 331 mixed ICU patients (medical, surgical, trauma, neuro) that investigated reduced versus full calorie feeding in patients who had hypophosphatemia after initiating nutrition support. Patients who had hypophosphatemia (PO4 < 2.0 mg/dl [0.65 mmol/L]) within 72 hours of starting nutrition support were randomized to either continuing full feeding, or calorie reduction.

The reduced-calorie group received 20 kcals/hour (480 kcals/24 hours) until phosphorus no longer needed to be replaced, and then calories were gradually increased (960 kcals/24hours, then 1440 kcals/24 hours, then 80% of goal calories X 24 hours, then goal calories). If hypophosphatemia reoccurred at any point during calorie increase, energy goals were returned to 480 kcals/24 hours. Patients in the standard care group received nutrition which “consisted of continuing nutritional support as planned before study enrolment” (calorie goals were not reported).

Thiamine, B-complex and a multivitamin with minerals were strongly recommended for all patients in the study.

The primary outcome was number of days alive after discharge from the ICU, at the 60 day follow-up. Secondary outcomes were major infectious complications, antibiotic treatment, insulin infusion requirements, daily blood glucose, daily dose of phosphate replacement, lowest daily serum potassium and phosphate concentrations, days of organ dysfunction by individual organ system, days of multiple organ dysfunction syndrome, and other concomitant ICU treatments.

Inclusion and Exclusion Criteria:

Inclusion criteria:

Critically ill adults who experienced a decrease in serum phosphorus below 2.0 mg/dl (0.65 mmol/L) within 72 h after starting nutrition support in a participating ICU.

Exclusion criteria:

Patients who received nutrition support prior to being admitted to the study ICU, receiving only palliative care or is moribund and not expected to survive, previous phosphorus repletion, or treatment for hyperphosphatemia, receiving renal replacement therapy, parathyroidectomy during admission, active treatment of hyperglycemia or ketoacidosis, brain death, previous enrollment into the study

Major Results:

Initially, 339 patients from 13 hospitals were enrolled, and after patients who withdrew consent, were lost to follow-up, or were incorrectly enrolled were excluded, a “modified intention to treat” analysis was completed on 331 patients (165 standard, 166 caloric management). Post randomization, 159 of the 166 patients in the calorie-management group (95.7%), had their calories appropriately adjusted per the protocol.

There were significant differences in total calorie provision between the two study groups on each of the 5 days of management (p=0·0001). Patients in the calorie-management group had a statistically significantly increased serum PO4 on days 1 and 2, compared to controls (Day 1: 2.2 versus 2.6 mg/dl; Day 2: 2.5 versus 2.8 mg/dl, respectively). Neither the phosphorus replacement dose, nor the number of patients who required phosphorus replacement were significantly different between study groups. There were no serious adverse events related to refeeding reported during the study.

The peak daily blood glucose measurements were significantly lower in patients in the caloric management group during the first 4 days (day 1: p=0·0007, day 2: p=0·0001, day 3: p=0·0001, day 4: p=0·0324), with significantly fewer patients in the calorie-management group with hyperglycemia, or needing insulin. Arterial lactate concentrations were significantly lower on days 2 (p=0·0001) and 3 (p=0·016) in caloric management patients compared to standard care patients.

There were no significant differences in mortality at ICU discharge or hospital discharge between the groups but there were significantly more of the calorie-managed group alive compared to the standard group at day 60 (p= 0.002) and day 90 (p= 0.004). There was no significant difference in ICU LOS between groups, but the calorie-management group had a significantly longer hospital LOS (p=0.003) compared to the standard group. Patients in the calorie-managed group were diagnosed with significantly fewer major acquired major infections, airway, or lung infections, although rates of other infections at different sites did not differ between groups.

Author’s Conclusions:

“…The Refeeding Syndrome Trial did not show any clinically important harm associated with short-term caloric restriction in critically ill patients with refeeding syndrome.… On the basis of these results, caloric restriction seems to be a suitable therapeutic option for adult critically ill patients with refeeding syndrome.”

Evaluation:

This study is a great example of both a) Why it is helpful for clinicians to read original research, and b) Sometimes the thing you did not expect to learn is more valuable than the information you thought you would learn.

Our group felt that the lack of any real clinical difference in serum phosphorus levels, no difference in requirement for phosphorus repletion and no difference in any signs of refeeding syndrome between the groups suggest that this study has much less to do with anything regarding refeeding syndrome, and much more about the potential benefits of initial hypocaloric feeding, especially in patients that may be malnourished.

Although there were trivial differences in serum phosphorus between the groups, the significant differences in serum lactate, serum glucose and insulin requirements between the groups were notable. While this study had a modest number of participants for mortality outcomes, the differences in infectious complications are interesting. It is certainly possible that malnourished-vulnerable populations in the ICU may benefit from a period of initial hypocaloric feeding regardless of electrolyte shifts or apparent signs of refeeding syndrome.

Our Take Home Message(s)

1. Decreasing calorie intake after feeding-associated electrolyte shifts are apparent does not influence requirements for electrolyte repletion or clinically apparent refeeding syndrome.
2. Decreased early calorie provision in patients who experience feeding-associated electrolyte shifts may decrease insulin requirements, improve glucose control and improve clinical outcomes.
3. This study may have been too small to reliably rule out effects related to chance differences between the groups.