There is documentation regarding the relation between protein energy malnutrition in chronic disease and increased morbidity and mortality.1 Protein energy malnutrition leads to an increased rate of infections, bed sores, muscular weakness, poorer respiratory function, hypotrophy of cardiac muscle, and death.1 Although the data regarding the effects of nutritional treatment are inconclusive, supplementary nutrition may prevent complications in patients with numerous chronic nonmalignant disorders.1 Protein energy malnutrition is seen more often in patients with hip fractures than in age-matched control subjects.3,13,14,19 Patients with hip fractures have suboptimal energy intake during the postoperative period,16,21,25 and deteriorate in nutritional status and functional condition after the fracture.13,18 Protein energy malnutrition is an important determinant of clinical outcome, including postsurgical complications such as impaired wound healing, infections, decubital ulcers, and death in older patients with hip fractures. 5,7,12,15,18,21,22,29
Despite these facts, elderly patients with hip fractures rarely receive nutritional assessments and adequate intervention seldom is provided.20,26 In a systematic review of randomized trials of patients 65 years and older with hip fractures, oral protein and energy supplementation reduced unfavorable outcomes but did not show an effect on mortality.2 Bastow et al recommended additional evidence from good quality randomized trials.2 We performed a randomized, controlled trial to determine if a combination of intravenous and oral nutritional supplementation during the first 10 days of hospitalization decreased fracture-related complications and mortality in a selection of otherwise healthy patients with hip fractures. We hypothesized that nutritional supplementation would reduce the risk of postoperative hip fracture complications and mortality.
MATERIALS AND METHODS
We evaluated patients older than 60 years with cervical or trochanteric hip fractures treated by the orthopaedic department of our institution. Written informed consent to participate was a prerequisite for participation as advised by the ethical committee. We included patients who had surgery less than 48 hours after trauma. The intention was to study comparatively healthy subjects with hip fractures who were able to give informed consent to participate, had no comorbidities that might be negatively influenced by the supplementary treatment regime, and who had no diseases or other fractures that might hamper normal mobilization. All exclusion criteria were prespecified in the study protocol. We excluded patients with multiple fractures, pathologic fractures, malignant disease, inflammatory joint disease, pain, or functional impairment other than the hip fracture which might hamper normal mobilization (n = 188). Patients with substantial cognitive impairments (n = 153), depression (n = 17), acute psychosis (n = 14), known alcohol or medication abuse (n = 6), and epileptic seizures (n = 1) also were excluded. We used a mini-mental test11 to exclude patients with substantial cognitive impairment. Patients with a score less than six points were classified as having substantial cognitive impairment and were excluded. Thirty-four patients refused to participate and 23 patients with ongoing warfarin treatment were excluded because they were not operated on within 48 hours after fracture. We also excluded patients with diseases of such severity that the patient might be negatively influenced by the supplementary treatment regime planned for the intervention group. This included patients with insulin-treated diabetes mellitus (n = 32), heart, kidney or liver insufficiency (n = 26), suspected acute myocardial infarction (n = 14), and hematemesis (n = 2). The risk of complications after hip fracture in the selection of included patients was unknown. Using a worst-case scenario with a 50% risk of complications without supplementation and a presumption that supplementation would halve the risk of complications, the number of patients needed to show a 90% power of achieving significant results at the 5% level was 18 patients per group.
A research nurse (UBO) randomized 80 patients to either a control or an intervention group using block randomization with 40 closed and numbered envelopes in each block. Twenty envelopes in each block had a note inside with control or intervention group, respectively.
The median age of the patients was 78 years in the control group and 84 years in the intervention group (Table 1). All patients were treated in the same unit in a nonblinded fashion. Perioperative care programs including intravenous infusion, antibiotic and thrombosis prophylaxis, and postoperative full weightbearing were the same in both groups. Nutritional status was evaluated by subjective global assessment (SGA), anthropometric measurements (arm muscle circumference, triceps skinfold thickness, and body mass index [BMI]), serum proteins (albumin, transthyretin), and total lymphocyte count.9 All tests and recordings were performed by the same nurse.
Both groups received hospital food and beverages. All meals and beverages had known energy (kcal) content. The nurses observed all meals and noted the contents of the patient's plate and beverages as the meal was issued and removed. The proportion of each component of the meal and beverage consumed was calculated on charts on a daily basis. The intervention group also received 1000 mL Vitrimix® (Kabi Pharmacia AB, Stockholm, Sweden) daily for 3 days from Day 1, followed by a 7-day oral intervention with Fortimel® (Nutricia AB, Numico, The Netherlands), 2 × 200 mL daily. Vitrimix® is an intravenous supplementary nutriment consisting of 250 mL IntralipidA® and 750 mL VaminA®-Glucose which, when aseptically mixed via the transfer set provided, produces an intravenous nutrition of 1 kcal/mL mixture suitable for infusion via a peripheral or central vein. The mixture also contains amino acids, sodium, potassium, calcium, magnesium, and chloride. Trace elements (Tracel®, Kabi Pharmacia AB), and water- and fat-soluble vitamins (Soluvit Novum® and Vitalipid Novum®, Kabi Pharmacia AB) were added to the Vitrimix® infusion according to the structured protocol and the manufacturers' instructions. Vitrimix® was administered by peripheral veins, with only one patient experiencing thrombophlebitis. Fortimel® is a nutritional supplement for oral intake. The energy content is 100 kcal/100 mL, including 10 g protein, 10.3 g carbohydrates, and 2.1 g fat, minerals, and vita- mins. The total approximate energy and fluid intake including food, beverage, snacks, Fortimel®, Vitrimix®, and other intravenous infusions was recorded daily. The optimal dietary intake was based on a basal demand of 25 kcal/kg body weight/day.23 The optimal fluid intake was based on the basal demand of 30 mL/kg body weight/day.4
The definition of each complication was based on clinical symptoms and signs and a positive objective investigation. The examinations that were done when a complication was suspected were decided by the physician in charge of the patient in question. All nurses and physicians were blinded to the provided treatment and to the results. All clinical data were viewed by one (UBO) individual who was unblinded to the treatments. The following complications were recorded at Day 3, Day 10, discharge, Day 30 and Day 120: (1) infections (wound infection, urinary infection, or pneumonia), (2) other complications (thrombophlebitis, deep venous thrombosis, pulmonary embolism, pulmonary edema, or myocardial infarction), and (3) death. The diagnoses of wound infection and urinary infection were based on clinical symptoms and signs and positive culture results. The diagnosis of pneumonia was based on clinical symptoms and signs and positive radiographs. The diagnosis of deep venous thrombosis was based on clinical symptoms and signs and a positive phlebography. The diagnoses of pulmonary edema, pulmonary embolus, and cardiac infarction were based on clinical symptoms and signs, supported by appropriate examinations (radiographs, pulmonary scintigraphs, electrocardiograms, and laboratory tests). All complications during hospitalization were recorded in the charts according to protocol by each patient's responsible nurse and/or physician. To be certain that all complications were included during hospitalization, one study nurse (UBO) checked daily to ensure proper and complete reporting. The same nurse performed the postoperative followups and recorded the complications.
The results are reported as mean ± standard deviation (SD) if not otherwise stated. Differences between or within groups were calculated using the t test or the chi square test with one DF (degrees of freedom) as appropriate.
There were no differences for gender, comorbidities, living conditions before fracture, hip fracture type, or time to surgery from trauma. The surgical methods used in cervical fractures were two hook pins (13 patients), hemiarthroplasty (22 patients), or total hip arthroplasty (THA) (five patients), with no differences in type of procedures between groups. Screw and plate fixation was used in all 40 patients with trochanteric fractures. The mean hospital stay was 12.5 days in both groups. Twenty-two patients (55%) were discharged to their own home in the control group compared with 14 patients (35%) in the intervention group.
There were no preoperative differences in signs of protein energy malnutrition between the intervention and control groups (Table 2). Abnormal values indicating protein energy malnutrition was present were seen in 9% of patients when using the selective global assessment Group B-C as the criteria, in 13% to 28% of patients in anthropometric tests, in 44% to 62% of patients in serum proteins, and in 78% of patients in total lymphocyte count. Fifteen patients (38%) in the intervention group and 13 patients (33%) in the control group had three or more abnormal nutritional parameters, strongly indicating protein energy malnutrition. Twenty-four patients (60%) in the treatment group and 23 patients (58%) in the control group had one to two abnormal nutritional parameters, indicating protein energy malnutrition. One patient in the treatment group and four patients in the control group had no abnormal nutritional parameters.
The average daily energy intake during the first 3 days was 665 kcal in the control group and 1468 kcal in the treatment group (p = 0.001). The average daily energy intake during Days 1 to 10 was 916 kcal/day in the control group compared with 1296 kcal/day in the treatment group (p = 0.003). The control group received 54% and the intervention group received 85% of the calculated daily optimal energy intake (p = 0.0003).
The average daily fluid intake during the first 3 days was 1704 mL in the control group and 2358 mL in the treatment group (p = 0.04). The average daily fluid intake in the control group during Days 1 to 10 was 1300 mL, compared with 1856 mL in the intervention group, (p < 0.0001). The control group received 64% and the intervention group received 101% of the calculated daily optimal fluid intake (p < 0.0001).
There were no differences between groups regarding serum hemoglobin, serum albumin, serum transthyretin, C-reactive protein, or total lymphocyte count at Days 1, 10, 30, and 120. Serum albumin, serum transthyretin, and total lymphocyte count decreased in both groups at Day 10, but increased to higher levels at Day 30 than at the time of inclusion in both groups. Six patients (15%) in the intervention group and 28 patients (70%) in the control group had at least one of the recorded complications (p < 0.0001). In the control group, 17 patients had one complication and 11 patients had more than one complication. Within 30 days, 33 complications (infections, other complications, and death) occurred in the control group compared with six complications in the intervention group (p < 0.0001) (Table 3). Of the 28 patients who preoperatively had three or more abnormal nutritional parameters and were classified as malnourished, 15 had at least one complication (54%), whereas 19 (37%) patients without protein energy malnutrition at inclusion had at least one complication until Day 120 (p = 0.14).
The cumulative number of infections was greater in the control group than in the intervention group at Days 10, 30, and 120 (Table 3). Five patients (13%) in the control group and none in the intervention group were diagnosed with pneumonia within 10 days postoperatively (p = 0.006). Twelve patients (30%) in the control group and two patients in the intervention group (5%) had wound infections within 30 days from surgery (p = 0.006).
Four patients in the control group died within 70 days (p = 0.04). The overall mortality was 1% within 30 days and 5% within 4 months. Three patients died of pneumonia and one died of general weakness and malnourishment.
The combined oral and parenteral nutritional supplementation increased the total fluid and energy intake in the intervention group to near optimal levels, whereas the control group received only 54% of the optimal energy and 64% of the optimal fluid intake. Patients in the intervention group had fewer fracture-related complications than patients in the control group at Days 10 and 30, at 4 months, and overall. Only 15% of patients in the intervention group had one or more complication compared with 70% of patients in the control group.
At least ⅓ of all patients were protein energy malnourished, and more than 1/2 of patients in both groups had evidence of malnourishment at inclusion. There was no difference regarding the risk of complications between patients classified as having protein energy malnutrition at inclusion compared with patients who did not have malnutrition (ie, the risk of complications does not primarily depend on preoperative nutritional status). During hospitalization the control group received only 54% of the optimal energy intake. These findings are in accordance with those in previous studies showing that patients with hip fractures more often have protein energy malnutrition3,13,14,19 and have suboptimal energy intake during the postoperative period.16,21,25 Because patients with hip fractures also deteriorate in nutritional status and functional condition after the fracture,13,18 and protein energy malnutrition is an important determinant of clinical outcome, 5,7,12,15,18,21,22,29 nutritional supplementation in patients with hip fractures has potential value.
Espaulella et al10 found oral nutritional supplementation to be useful in decreasing complications in patients in a randomized, double-blind, placebo-controlled trial. Because this reduction did not improve the functional recovery or mortality, they reported routine nutritional supplementation cannot be recommended for all elderly patients with hip fractures.10 However, only 8% were considered undernourished in both groups. The extra energy intake was only approximately 150 kcal/day if taken at all, and did not differ between groups other than the protein, calcium, and vitamin D3 intake. No data are available regarding the actual protein energy intake during the 60 days of treatment.10
In previous clinical trials of nutritional oral supplementation to patients with hip fractures, patients in four studies had a shorter hospitalization period,3,8,24,28 patients in three studies had fewer postoperative complications such as infections, delirium, and bed sores,8,10,28 and patients in one study seemed to experience beneficial effects from the supplementation on their mortality.27 However, the lack of an established definition of malnutrition, variations in the type and duration of nutritional intervention, and different outcome parameters make conclusions based on existing studies weak. The effectiveness of nutritional support programs in patients with hip fractures is controversial, and additional evidence from good quality randomized trials is recommended.2,6
We are the first to report the results of intravenous and oral nutritional supplementary intervention in patients with hip fracture-related complications. In a prospective, randomized, controlled, clinical trial, we used intravenous nutritional supplementation for the first 3 days because the oral intake during that time is limited because of pain, fasting, and surgery. The first 3 days of supplements were followed by 1 week of enteral supplementary treatment. Poor compliance with oral supplements is regarded as an important determinant of the effectiveness of oral nutrition in preventing complications after hip fracture.6 This was not an issue in our study as all patients received the supplementary nutrition while hospitalized and none had mental impairment.
Although it is likely that it is the overall nutrition status that is essential for optimal health and healing, the emphasis in previous studies evolves around protein energy malnutrition.3,5,7,12-15,18,19,21,22,29 The supplementation our patients received was not only a protein- and energy-rich supplement, but a balanced protein and energy supplement complete with vitamins and minerals. Whether it was the increased balanced overall caloric intake and/or hydration that counteracted the effects of low nutritional status rather than the protein is unknown. The fluid intake was only 64% of optimal in the control group versus 101% in the intervention group. It is likely that the combination of increased energy intake and hydration along with the increased protein intake and the vitamin-mineral mix was responsible for the decreased infection rates.
The patients' nurse or physician recorded complications during and after hospitalization until Day 120. Even though the patients and investigators were nonblinded, the nurse and physician responsible for documenting complications were not part of the research group. We think the risk of bias was small.
The overall low mortality in both groups is ascribed to the selection of comparably healthy patients. All four patients who died during the 4-month study were part of the control group despite being an average of 6 years younger at inclusion. Other than the lower mean age of patients in the control group (suggesting the potential for decreased risk of complications), there were no other differences in patients and fracture characteristics between groups other than fluid and energy intake. This indicates fluid and/or nutritional supplementation may be responsible for the difference in outcome between groups despite the discrepancy of time of nutritional supplementation and the lag time in complication reduction for mortality.
We studied a selection of healthy patients with hip fractures. Patients were excluded if they had functional impairments, mental impairments, or diseases that may have been negatively influenced by the supplementary treatment regime. We included 80 of 590 patients (14%) older than 60 years treated for a cervical or trochanteric hip fractures that were less than 24 hours old. This selection of the most healthy patients with hip fractures may be a concern regarding the generality of the effect of our treatment regime in a more typical population with hip fractures. However, we think this makes our findings even more interesting as the group of patients most likely having protein energy malnutrition and most likely to experience complications and mortality were excluded. Had these patients been included, the effect might have been more obvious. The nutritional regime also would be applicable to less fit patients. Providing intravenous supplementation does not need the cooperation of the patient, and ingestion of the oral supplement could be supervised.
We think the reduced complication rate in the intervention group justifies the use of nutritional supplementation in patients with hip fractures. Given the increasing number of elderly patients with hip fracture each year, the high prevalence of protein energy malnutrition, and the increased risk of morbidity associated with poor nutrition, nutrition guidelines must be established based on validated evidence.17,27
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