A Randomized, Double-Blind, Placebo-Controlled Trial of Nutritional Supplementation During Acute Illness
Article Outline
Abstract
Purpose
The study tested whether nutritional support of older patients during acute illness leads to a clinical benefit.
Methods
In this randomized, double-blind, placebo-controlled study, we randomly assigned 445 hospitalized patients aged 65 to 92 years to receive either a normal hospital diet plus 400 mL oral nutritional supplements (223 subjects) or a normal hospital diet plus a placebo (222 subjects) daily for 6 weeks. The composition of the supplement was such as to provide 995 kcal of energy and 100% of the Reference Nutrient Intakes for vitamins and minerals for a healthy older person. Patients had three assessments: at baseline, at 6 weeks, and at 6 months post-randomization. Outcome measures were 6 months of disability, non-elective readmission and length of hospital stay, discharge destination, morbidity, and mortality.
Results
Randomization to the supplement group led to a significant improvement in nutritional status. Over 6 months, 65 patients (29%) in the supplements group were readmitted to the hospital compared with 89 patients (40%) in the placebo group (adjusted hazard ratio 0.68 [95% confidence interval 0.49-0.94]). The mean length of hospital stay was 9.4 days in the supplements group compared with 10.1 days in the placebo group. Thirty-two people (14%) died in the supplement group compared with 19 people (9%) in the placebo group at 6 months (adjusted hazard ratio 1.65 [95% confidence interval, 0.93-2.92]).
Conclusion
Oral nutritional supplementation of acutely ill patients improved nutritional status and led to a statistically significant reduction in the number of non-elective readmissions.
Keywords: Nutritional supplements, Acute illness, Clinical outcome, Readmission
The number of older people is growing rapidly worldwide. With advancing age, both undernutrition and chronic diseases become more common.1
There is evidence linking protein–energy undernutrition or its markers with clinical outcomes in acute and non-acute care settings.2, 3, 4, 5, 6, 7 In the hospital, the nutritional status of elderly patients is likely to deteriorate further because of the catabolism associated with acute illness.3, 4 Recent studies have found protein–energy undernutrition to be a strong predictor of in-hospital and postdischarge clinical outcome.5, 6, 8 Similarly, elderly patients with poor nutritional status during the first month after hospitalization also have been shown to be at a much higher risk of non-elective readmission.9 A systematic review reported that in elderly people at risk of undernutrition, supplementation of protein and energy shortened hospital stay; however, few data were reported on morbidity and functional status.10
The aim of this double-blind, placebo-controlled, randomized trial was to assess whether nutritional support during acute illness, and extending through the period of convalescence, led to improvement in clinical outcome.
Methods
Study Population
We randomized hospitalized patients aged 65 years or more to a normal hospital diet plus placebo (n = 222) versus a normal hospital diet plus oral supplements daily for 6 weeks (n = 223). Inclusion criteria were age 65 years or more, able to swallow, and able to sign an informed written consent form. Patients excluded from the study were those who had undergone gastric surgery, with diagnosed malabsorption or morbid obesity (body mass index > 40), in a coma, with diagnosed severe dementia (abbreviated mental test < 6) and malignancy, living in an institution, and already taking supplements. The study was approved by the Barnsley Research Ethics Committee, and informed written consent was obtained from each patient.
Treatment and Placebo
The supplement group received 2 bottles (200 mL each) of oral nutritional supplement daily at 8:00 a.m. and 12 noon in addition to the standard hospital diet for a period of 6 weeks. The composition of the supplement was such as to provide 995 kcal for energy and 100% of the Reference Nutrient Intakes for vitamins for a healthy older person. The placebo was identical to the supplement but contained no protein or micronutrients and with a minimum calorie content (60 kcal). Samples of the trial placebo, supplements, and other commercially available food supplements were piloted in 15 volunteers. No patients, research assistant, investigator, or any other medical or nursing staff could distinguish the placebo from the supplements during the study.
Dietary intakes of the study population were measured using a validated food diary.11 All patients had prescribed supplement bottles collected during the study period, and leftover supplements were measured.
Clinical Assessment and Follow-Up
The main outcome measures were 6 months of disability (Barthel score), non-elective readmission and length of stay in hospital, discharge destination (own home or institution), morbidity (infective complications), and mortality. Disability was assessed using the Barthel score on a 20-point scale. The Barthel scores 10 functions on a scale from 0 (fully dependent) to 20 (independent).12 Nutritional status was assessed from anthropometric, hematologic, and biochemical data. All anthropometric measurements were performed by S. F. using standard methods with intraobserver’s differences assessed before the commencement of the study. The interassay coefficient of variation was 2% for serum albumin, 7% for transferrin, 12.6% for red cell folate, and 8.4% for plasma vitamin B12. The interassay coefficient of variation was 3.9% for C-reactive protein concentration.
Statistical methods
Randomization
The randomization sequence was generated by the trial statistician; concealed in sequentially numbered, sealed opaque envelopes; and kept in a clerical office at a different city. Contact was made by telephone for a trial medication number, and patient baseline details were recorded in the database.
Sample Size Calculation
In patients who have had a stroke, we previously showed that a 1 g/L lower serum albumin concentration in the hospital is associated with a 1.13-fold increase in the risk of death (95% confidence interval [CI] 1.01-1.27).3, 4 Therefore, a sample size of 438 (219 in the supplements group and 219 in the control group) would allow the detection of a true mean difference in serum albumin of 1 g/L (assuming a within-group standard deviation of 3.5 g/L and 10% loss to follow-up), with 80% power and 5% (2-sided) significance. This sample size also would allow for the detection of a 1.5-point difference in disability, as measured by the Barthel score at 6 months (assuming a within-group standard deviation of 5.0) with 80% power and 5% (2-sided) significance.
Quality Assurance
The trial statistician carried out an interim and end-of-study blind validation of collected data. Two researchers independently checked hospital records for all routinely collected outcome measures. Agreement was 99%.
Analyses
All statistical analyses were done with blinding maintained and on an intention-to-treat basis with a P value of less than .05 regarded as statistically significant. A Cox proportional hazards model was used to examine the 6-month risk of non-elective readmission and mortality between the 2 groups after controlling for a number of non-nutritional factors such as age, disability, chronic illness, drugs, smoking, and tissue inflammation.
Results
Between March 2001 and January 2004, 445 patients aged 65 to 92 years were recruited. Figure 1 details the recruitment and intervention process and 6-month follow-up.
Figure 1.
Enrollment, treatment, and follow-up of study patients.
Baseline Characteristics of Study Population
The 2 groups were comparable with respect to baseline disability, smoking, drug and alcohol intake, dietary intake, and nutritional status (P > .05). Although the patients in the supplement group were older and had higher C-reactive protein and serum ferritin concentrations, lower transferrin concentrations, and a high prevalence of chronic diseases compared with the placebo group, these baseline differences did not reach statistical significance except for serum ferritin and transferrin concentrations (Table 1). Figure 2 shows adherence to supplement and placebo treatments expressed as the percentage of patients consuming drinks, divided into quartiles. Nausea was the most common side effect, reported by 22% of the patients with no difference between the supplement and placebo groups.
Table 1. Baseline Characteristics of Patients
| Placebo | Supplements | P Value | ||||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| Gender | Male | 119 | (53.6%) | 115 | (51.6%) | .7 |
| Female | 103 | (46.4%) | 108 | (48.4%) | ||
| Smoking | Never smoked | 58 | (26.7%) | 79 | (36.4%) | |
| Ex-smoker | 116 | (53.5%) | 100 | (46.1%) | ||
| Current smoker | 43 | (19.8%) | 38 | (17.5%) | .1 | |
| Residence | Own home | 141 | (65.0%) | 123 | (56.7%) | .1 |
| before | Own home with carer | 19 | (8.8%) | 28 | (12.9%) | |
| hospitalization | Sheltered housing | 35 | (16.1%) | 40 | (18.4%) | |
| Assistance at home | 22 | (10.1%) | 26 | (12.0%) | ||
| Chronic illness/patient | 1.7 | 1.9 | .6 | |||
| Drugs/patient | 3.5 | 3.5 | .9 | |||
| Admission diagnosis | ||||||
| IHD (MI and angina) | 29 | (13.3%) | 30 | (13.8%) | .9 | |
| Fracture neck of femur | 9 | (4.1%) | 9 | (4.1%) | .9 | |
| Syncope | 2 | (.9%) | 7 | (3.2%) | .1 | |
| Atrial fibrillation | 8 | (3.7%) | 11 | (5.1%) | .5 | |
| Stroke | 12 | (5.5%) | 5 | (2.3%) | .1 | |
| Fall | 13 | (6.0%) | 12 | (5.5%) | .8 | |
| COPD | 25 | (11.5%) | 39 | (18.0%) | .1 | |
| Chest infection | 21 | (9.6%) | 18 | (8.3%) | .6 | |
| Urinary tract infection | 5 | (2.3%) | 9 | (4.1%) | .3 | |
| Elective surgery knee | 14 | (6.4%) | 13 | (6.0%) | .9 | |
| Elective surgery hip | 11 | (5.0%) | 8 | (3.7%) | .5 | |
| Heart failure | 17 | (7.8%) | 19 | (8.8%) | .7 | |
| Miscellaneous | 52 | (24%) | 37 | (17%) | .1 | |
| Mean | SD | Mean | SD | |||
| Age (y) | 76.3 | (6.1) | 77.1 | (6.3) | .2 | |
| Barthel score | 16.1 | (4.5) | 15.8 | (4.7) | .9 | |
| CRP (mg/L) | 48.8 | (66.8) | 55.6 | (79.6) | .5 | |
| Dietary intake (kcal) | 1653 | (399) | 1672 | (345) | .1 | |
| BMI (kg/m2) | 25.2 | (4.1) | 25.0 | (4.3) | .6 | |
| Weight (kg) | 66.7 | (13.1) | 65.7 | (13.7) | .4 | |
| MUAC (cm) | 28.3 | (3.5) | 28.0 | (3.8) | .5 | |
| TSF (mm) | 15.8 | (6.6) | 15.5 | (6.5) | .9 | |
| Albumin (g/L) | 37.8 | (4.6) | 37.9 | (4.7) | .6 | |
| Transferrin (g/L) (baseline) | 2.2 | (.5) | 2.1 | (.5) | .05 | |
| Ferritin (μg/L) | 169.6 | (234.6) | 181.8 | (199.3) | .03 | |
Figure 2.
Adherence to supplements and placebo (maximum 84 drinks).
Nutritional Outcomes
At the 6-month follow-up there were no statistically significant differences between the supplement and placebo groups in body weight, body mass index, mid upper arm circumference, triceps skinfold, or transferrin. Serum albumin concentration increased significantly in the supplement group (Table 2). Both red-cell folate and plasma vitamin B12 concentrations significantly improved in the supplement group compared with the decrease seen in the placebo group (Figure 3).
Table 2. Effect of Supplements on Main Outcome Measures Compared with Placebo at 6 Months
| Outcome Measure | Placebo | Supplements | P Value | |||
|---|---|---|---|---|---|---|
| No. | Mean (SD) | No. | Mean (SD) | |||
| Nutritional | Body mass index | 106 | 26 (4) | 119 | 26(4) | .6 |
| Body weight(kg) | 106 | 69(13) | 119 | 69(14) | .9 | |
| MUAC(cm) | 106 | 28.6(3) | 119 | 28.3(4) | .4 | |
| TSF(mm) | 106 | 15.6(7) | 119 | 15.3(6) | .9 | |
| Serum albumin (35-55 g/L) | 106 | 40.5(4) | 119 | 42(4) | .04 | |
| Serum transferrin (2-4 g/L) | 106 | 2.59(0.6) | 119 | 2.4(0.5) | .3 | |
| Clinical | Barthel score | 223 | 18.6(3) | 222 | 18.3(3) | .9 |
| Length of stay(d) | 223 | 10.1(8) | 222 | 9.4(7) | .2 | |
| No. of infections | 223 | 26(12%) | 222 | 21(10%) | .4 | |
| No. of readmission | 223 | 89(40%) | 222 | 65(29%) | .02 | |
| No. of deaths | 223 | 19(9%) | 222 | 32(14%) | .1 | |
Figure 3.
Effect of supplements on red-cell folate and plasma vitamin B12 concentrations compared to placebo.
Clinical Outcomes
The proportion of patients readmitted to the hospital at 6 months was significantly lower in patients randomly assigned to nutritional supplements (29%) compared with those in the placebo group (40%) (P < .05). Figure 4 shows the risk of readmission for supplement and placebo groups over the 6-month period. Cox regression analysis showed that the risk of non-elective readmission in the 6-month follow-up period was significantly lower in the supplement group than in the placebo group after adjustment for other clinical risk indicators, with a hazard ratio of 0.68 (95% CI, 0.49-0.94). No other clinically important difference between the supplement and placebo groups was found in length of stay in hospital, infections, disability, discharge destination, or mortality (Table 2). The death rate was higher at 6 months in the supplement group (32/223; 14%) compared with the placebo group (19/222; 9%) (P value = .06). After adjustment for other clinical risk indicators, Cox regression suggests that the hazard or risk of dying, up to 6 months postrandomization, was 1.65 times higher (95% CI, 0.93-2.92, P = .09) in the supplement group compared with the placebo group.
Figure 4.
Kaplan-Meier curve for 6-month readmission.
Discussion
The results of this study indicate that nutritional supplementation of older people during acute illness and the convalescence/rehabilitation period significantly reduces non-elective 6-month readmission rates. These clinical benefits were observed despite the modest degree of adherence to taking the supplements. The improvements in readmission rate indices were accompanied by significant improvements in biomarkers of nutritional status in the supplement group, which were evident at 6 weeks and sustained at 6 months.
Improvement of nutritional status, immune function, and well-being would be the most plausible explanation for the results presented here. The lack of statistically significant differences in anthropometric measures between the supplement and placebo groups could be the result of the short time-frame of the supplementation and the inherent difficulties in measuring these nutritional indices in aging patients. This is especially true for studies in the elderly, who are affected by age-related changes, disability, illness, and injury. Distinguishing underlying disease from undernutrition and separating their effects on the aging patient’s outcome have always been challenges for clinicians.13, 14 Another plausible explanation for our results would be that mild subclinical nutritional deficiencies, which are known to be common even in relatively healthy persons and otherwise would have gone unnoticed in our supplement group, have been corrected, thus the clinical benefit.15
Mortality was nonsignificantly higher in the supplement group compared with the placebo group. Can increased mortality be an indicator of risks and benefits associated with the supplements in this trial? For supplements to have an effect on mortality in such a high-risk group of patients, this can only occur when patients have taken sufficient amounts and there is a biologic plausibility for this effect on mortality. In this trial, 12 deaths in the supplements group and 7 deaths in the placebo group occurred within the first 6 weeks after randomization. Furthermore, 15 of those who died in the supplement group consumed 3 or fewer of 84 drinks prescribed.
Strengths and Weaknesses
We believe this study to be the first randomized, double-blind, placebo-controlled trial to compare the effect of a 6-week protein, energy, and micronutrient supplementation on the medium-term clinical outcome of hospitalized elderly patients. Despite the modest adherence to the full amount of prescribed supplements, we compared the group randomly allocated to supplements with the group allocated to placebo. This approach, in addition to being unbiased, provides a pragmatic answer to the question of primary clinical interest in this trial, for example, does nutritional supplementation of older patients during acute illness and convalescence/rehabilitation periods have a clinical benefit? Adherence to nutritional supplements by older people is known to be poor even when the supplements are prescribed in the drug charts and issued by the nursing staff to patients with their prescribed medications and with continuous prompting from the research dietician.16, 17
Future research should focus on understanding the complex factors that determine the intake of food in the aging population, such as the effect of improved palatability on stimulating food intake and screening tools for acceptability of such products by the elderly.
We cannot exclude the possibility that the decreased readmission rates as a result of nutritional support is a chance finding; however, it is also possible that it is a real one given the improvement in micronutrient status and the fact that mild subclinical nutritional deficiencies are known to be common even in relatively healthy older persons.15 Our inclusion criteria and baseline characteristics suggest that our study population represent a better-nourished group of patients. By contrast, those who were excluded because of severe illness, dementia, supplement intake, or living in institutional care were more likely to be undernourished and may therefore benefit most from nutritional support.
Conclusion
This trial demonstrated that nutritional supplementation of hospitalized elderly people leads to a clinically important benefit. Widespread implementation of this strategy, taking into account patients’ preference, lifestyle, and socioeconomic circumstances, could have a substantial economic impact and improve the quality of life for older people.
Acknowledgments
Salah Gariballa was the lead investigator and prepared the first draft of the article. Sarah Forster undertook subjects’ recruitment and assessments. Stephen Walters was responsible for statistical analysis. Hilary Powers was a co-investigator. All investigators were involved in the study design and writing of the article.
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PII: S0002-9343(05)01153-8
doi:10.1016/j.amjmed.2005.12.006
© 2006 Elsevier Inc. All rights reserved.
