Malnutrition in the Critically Ill Child: The Importance of Enteral Nutrition
2011. 2011

Marta Botrán Prieto
Pediatric Intensive Care Department, Hospital General
Universitario Gregorio Marañón
No. 47 Doctor Castelo28009MadridSpain

Jesús López-Herce Cid
Servicio de Cuidados Intensivos Pediátricos, Hospital General Universitario Gregorio Marañón, No. 47 Doctor Castelo
28009MadridSpain

International Journal of Environmental Research and Public Health

Malnutrition in the Critically Ill Child: The Importance of Enteral Nutrition

Int. J. Environ. Res. Public Health
82011. 201110.3390/ijerph8114353Received: 25 October 2011; in revised form: 15 November 2011 / Accepted: 15 November 2011 /Review * Author to whom correspondence should be addressed; E-Mail: firstname.lastname@example.com; 4354nutritionmalnutritionenteral nutritionparenteral nutritioncritically ill children
Malnutrition affects 50% of hospitalized children and 25-70% of the critically ill children. It increases the incidence of complications and mortality. Malnutrition is associated with an altered metabolism of certain substrates, increased metabolism and catabolism depending on the severity of the lesion, and reduced nutrient delivery. The objective should be to administer individualized nutrition to the critically ill child and to be able to adjust the nutrition continuously according to the metabolic changes and evolving nutritional status. It would appear reasonable to start enteral nutrition within the first 24 to 48 hours after admission, when oral feeding is not possible. Parenteral nutrition should only be used when enteral nutrition is contraindicated or is not tolerated. Energy delivery must be individually adjusted to energy expenditure (40-65 kcal/100 calories metabolized/day) with a protein delivery of 2.5-3 g/kg/day. Frequent monitoring of nutritional and metabolic parameters should be performed.

Introduction

Malnutrition affects millions of children throughout the World. Recently, the humanitarian organization Save the Children warned that "chronic malnutrition affects 178 million children in the World and is the third cause of all childhood deaths worldwide" [1].

Children under 5 years of age in developing countries are particularly vulnerable to malnutrition. However, malnutrition also exists in children in developed countries, in families with few resources or due to disturbances of feeding behavior or diseases that affect eating or the absorption of nutrients.

Infants and children are very susceptible to problems of nutrition. In comparison with adults, children have lower percentages of muscle mass and fat and therefore have fewer reserves and higher resting energy expenditure. For this reason, children have a poorer tolerance to fasting than adults, they are particularly susceptible to protein depletion, and they have an increased risk of developing malnutrition when they suffer serious illness [2]. It must not be forgotten that children are in a growth and development phase, with nutritional requirements that are greater and clearly differentiated from those of adults and that vary according to the stage of growth.

In the ill child, malnutrition is usually of multifactorial origin. It is associated with an altered metabolism of certain substrates, increased or decreased metabolism and catabolism depending on the severity and kind of the lesion, and reduced nutrient delivery. The presence of malnutrition prior to admission worsens the prognosis in the critically ill child and, furthermore, severe illness has marked repercussions on the nutritional status of these patients [3].

Malnutrition interferes with the appropriate response of the body to disease and predisposes to infection and to the onset of multiorgan failure, increasing morbidity and mortality, the mean length of hospital stay, and health costs [2,[4][5][6][7].

Incidence of Malnutrition in Hospitalized Children

Malnutrition is common at the time of hospital admission and tends to increase during the hospital stay. In Europe and North America, 40% to 50% of hospitalized patients can be at risk of malnutrition.

A number of studies have demonstrated that malnutrition affects 50% of children and adolescents during their hospital admission. The incidence of malnutrition in the critically ill child varies between 25% and 70% depending on the series [2,[6][7][8][9][10][11].

Improvements in the evaluation and monitoring of the nutritional status in the critically ill or chronically ill child, and individualization of nutritional treatment in these patients, appears to have reduced the prevalence of malnutrition in paediatric intensive care units (PICU) to some extent. However, the figures continue to be very high [11][12][13].

Types of Malnutrition in Children

Strictly speaking, the term malnutrition refers to any type of alteration of the nutritional status and includes nutritional deficiencies, obesity, and the use of inappropriate diets. However, the term is typically used to refer to nutritional deficiencies.

Nutritional deficiency has traditionally been defined in two ways, depending on the underlying deficit: calorie malnutrition or marasmus and protein malnutrition or kwashiorkor. Marasmus is caused mainly by a deficit in energy provision and is characterized by a pronounced loss of fat and muscle, leading to emaciation, with the child acquiring a cachectic appearance. Apart from their low weight and height for age, children with energy malnutrition present marked weakness and suffer frequent infections. Other symptoms include dry and wrinkled skin, bradycardia, and bradypnoea.

Kwashiorkor is caused by protein deficiency and is characterized by a loss of appetite, apathy, fluid retention and oedema, alterations of the skin, changes in hair colour, anaemia, and diarrhoea.

However, this clinical classification is subjective and it must also be taken into account that combined clinical states of protein and energy malnutrition are very common. Protein-energy malnutrition, in which there is a combination of energy deficit and, to a lesser degree, protein deficit, is the most important and common form of malnutrition.

Malnutrition can be classified according to its origin as primary, when the cause is a deficit in delivery (inadequate ingestion or gastrointestinal disorders), and secondary, when there is an underlying chronic disease or disorder that causes the malnutrition.

Malnutrition can also be classified as acute or chronic according to the time of onset and duration of the condition. Acute malnutrition occurs when there are recent deficits of supply or the sudden onset of an extensive lesion that leads to high levels of catabolism, whereas chronic malnutrition or growth delay is due to a persistent deficit in nutrient delivery, chronic disease, or acute disorders with a prolonged clinical course [5]. Acute malnutrition mainly affects weight whereas chronic nutrition affects both weight and height in children.

Other forms of malnutrition arise due to specific deficiencies of certain micronutrients, such as the vitamins or minerals. The most common deficiencies in the community are of vitamin A, iron, and iodine, although alterations of magnesium, zinc, and copper are also common in the critically ill child.

Risk Factors for Malnutrition in the Critically Ill Child

There are numerous factors that contribute to the onset of malnutrition in children admitted to intensive care. The incidence of malnutrition is higher in children under two years of age, in those with a prolonged hospital stay, and in those who require mechanical ventilation. Children with congenital heart disease and extensive burn injuries are also at increased risk of malnutrition [11].

An additional factor is that critically ill children frequently receive an insufficient calorie and protein delivery because enteral or parenteral nutrition cannot be initiated due to gastrointestinal intolerance or the need to restrict fluid intake, initiation is delayed, or there are interruptions in enteral nutrition in order to administer medication or to perform interventions requiring sedation [14].

Diagnosis of Malnutrition

The diagnosis of malnutrition in the ill child must be based on an objective evaluation of the nutritional status; this includes an adequate history of recent food intake and weight loss, anthropometric measurements, analysis of biochemical parameters and cellular immunity, and calculation of the body composition [8,15]. An adequate nutritional evaluation is essential in order to institute early nutritional intervention [8,11,16,17].

Anthropometric Measurements

Anthropometric evaluation is the simplest method for evaluating the nutritional status of a child. It has the advantages of being applicable to all patients, it is non-invasive, and it is not an expensive technique [16]. Anthropometric measurements in the child are more quantifiable and practical in the outpatient clinic and the World Health Organization therefore recommends the use of the following indices: weight for age, height for age, weight for height, mid-upper arm circumference, and birth weight.

The weight and height of the patient at the time of hospital admission allow us to perform a simple evaluation of the nutritional status and to calculate a number of nutritional indices. Weight is a good parameter for evaluating the effectiveness of nutrition in the child, though it is difficult to measure in the critically ill child on mechanical ventilation and with numerous catheters. Furthermore, it has a low sensitivity in the short term, and can be affected by variations in body composition (oedema or dehydration) without indicating changes in the nutritional status [16,18].

Measurement of the skinfolds is a cheap and relatively easy technique for studying the protein and fat components of the body; this is useful for the evaluation and monitoring of nutritional status [19]. The most widely used parameters are the tricipital skinfold thickness and mid-upper arm circumference. However, the measurement and interpretation of skinfold thickness has significant limitations in critically ill patients, as oedema increases the thickness of the fold, leading to overestimation of the nutritional status. In addition, skinfold parameters have a low sensitivity for short-term changes in the nutritional status.

Haematological Parameters

Haematological parameters are of very little value in the nutritional evaluation of the critically ill child as other factors such as haemorrhage, recent surgery, blood extractions, chronic infection or inflammation, and blood transfusions will alter their values to a much greater degree than the nutritional status [16].

Biochemical Parameters

In contrast, biochemical parameters are useful for evaluating and monitoring a patient's metabolism during hospital admission. Very low plasma concentrations of cholesterol and lipoproteins have been found in critically ill adults; these changes are due to an interruption of the enterohepatic circulation secondary to fasting or parenteral nutrition, infection, the administration of antibiotics, intestinal bacterial overgrowth, and multiorgan failure [20]. Some studies have found low values of total cholesterol, LDL-cholesterol, HDL-cholesterol, and apolipoprotein B in critically ill adults, with normal apoprotein A-I and triglyceride levels [20]. In children, low cholesterol and triglyceride levels are also common at the time of admission but they increase significantly with enteral nutrition, suggesting good lipid metabolism [16,[20][21][22]. It is also common to detect high triglycerides levels in relation to inflammatory states [23].

Hyperglycaemia is a common finding in critically ill children in the first 48 hours of their admission and is usually due to resistance or a decreased sensitivity of the tissues to insulin [16,17,21,22,24]. However, after this initial period, critically ill children usually show good tolerance to enterally administered carbohydrates [16,21,22]. Blood glucose values are therefore not good indicators of the nutritional status of the critically ill patient.

The Creatinine/Height Index measures global muscle catabolism and its values are affected by the quantity and type of proteins in the diet. In the critically ill patient, the creatinine/height index is able to detect malnutrition on admission, but its value as a variable for monitoring patients is an unresolved issue and also is not useful in renal failure [4,23]. Some studies suggest that a fall in the creatinine/height index could be an indicator of a risk of death, though other studies have not confirmed these findings [16].

The Nitrogen Balance is not a valid parameter for the diagnosis of malnutrition, although it can be used to control nutritional treatment and as a nutritional prognostic indicator (4). However, it must be taken into account that the critically ill patient presents acute phases of catabolism during which there is a negative nitrogen balance. Although the aim of nutrition is to achieve a positive or neutral nitrogen balance through an adequate energy and protein delivery, the hypercatabolic state that develops in the critically ill child as a response mechanism to the aggression cannot be initially blocked despite adequate protein delivery. At later stages a positive nitrogen balance can be reached with an adequate nutrition delivery [7,16,21,23].

Certain serum proteins (albumin, pre-albumin, transferrin, and retinol binding protein) can be good nutritional indicators in the critically ill patient. They reflect the ability of the liver to incorporate amino acids into protein synthesis, their half-life is not very long, and their concentrations fall rapidly in acute disease and recover in a relatively short time [7,16]. However, no relationship has been found between changes in the levels of these proteins and the nitrogen balance [16,21].

Albumin is a parameter that is widely used in nutritional evaluation due to its high specificity. However it has a low sensitivity as a nutritional marker as it has a long plasma half-life (20 days) and therefore is not a good parameter for monitoring nutritional status due to its low sensitivity to acute changes [4]. Other body proteins with shorter half-lives are better alternatives for evaluation of the protein nutritional status in the critically ill patient.

Pre-albumin, with a short half-life of two days and a small volume of distribution, is very sensitive and specific to changes in the nutritional status. Variations in its concentration can be observed in less than seven days after changes in the diet, and some studies report a good correlation between the levels of this protein and the nitrogen balance [16,21,[25][26][27]. Pre-albumin is a useful parameter for monitoring, re-nutrition and the evolution of nutritional status of the seriously ill patient and is the only valid parameter for evaluation of the nutritional status in renal failure [4].

Transferrin, the iron transport protein, has a short half-life of eight to ten days, and a small volume of distribution. However, its value as a nutritional indicator is lower than that of pre-albumin due to its low sensitivity and specificity when analyzed individually. Its levels are altered in liver disease, iron deficiency anaemia, nephrotic syndrome, and by multiple transfusions or the administration of aminoglycosides and cephalosporins. Even so, in the absence of alterations of iron metabolism, the transferrin concentration is a parameter that provides an adequate evaluation of the protein nutritional status. The rapid increase in transferrin and pre-albumin on starting enteral nutrition supports the hypothesis that when the energy and protein delivery is adequate in the critically ill child, hepatic synthesis of body proteins is rapidly stimulated, leading to a rise in their serum concentrations [16,21,27].

Retinol binding protein has a very short half-life of 12 hours, and its levels fall with malnutrition; however, levels also fall with liver disease, infection, and with intense stress. Retinol binding protein is a good marker of the nutritional status evolution and re-nutrition, but is not of value in patients with renal failure [4].

Fibronectin is synthesized in endothelial cells, hepatocytes, macrophages, and fibroblasts and it has a short half-life of between four and 24 hours. During fasting and in patients with malnutrition, fibronectin levels fall earlier than those of other proteins synthesized in the liver, and increase rapidly after restoration of an adequate energy delivery. It is considered to be a good marker of the nutritional status, although its concentration also falls in numerous acute diseases, such as sepsis and burns, and also in the postoperative period [16,25].

Alterations in electrolyte and mineral levels are common in the critically ill patient, but these changes are not generally secondary to problems of nutrition.

The incidence of hypocalcaemia, hypophosphataemia, and hypomagnesaemia is high in the critically ill child [24]. The most common causes of hypocalcaemia in the critically ill patient are cardiac surgery, sepsis, multiple transfusions, severe pancreatitis, acute renal failure, severe trauma, and multiorgan failure. Hypophosphataemia is usually secondary to fasting, to an increase in anabolism, which increases phosphate consumption, to the intravenous administration of glucose, or to diarrhoea [16,24]. The most common causes of hypomagnesaemia in the critically ill patient are a reduced delivery, the use of loop diuretics, extracorporeal surgery, and diarrhoea. Surgery and infections lead to a fall in the serum concentrations of zinc and iron due to hepatic redistribution and to the binding of iron to ferritin and of zinc to metallothionein. In the case of copper, the levels rise due to an increased synthesis of ceruloplasmin as an acute-phase reactant. However, the most common cause of zinc and copper deficiency is a reduced supply [16,24].

Repercussions and Complications of Malnutrition in the Critically Ill Child

In the critically ill child, complex metabolic changes occur in order to mobilize the substrates necessary for defense of the body against aggression. Two different phases can be identified in this response of the body to disease: an initial phase of a few hours during which there is a rapid fall in the metabolic rate, with a decrease in oxygen consumption and in energy production; and a second phase, regulated by hormonal changes, during which there is hypercatabolism with a negative nitrogen balance, loss of weight and muscle mass, and altered dynamics of carbohydrate metabolism [8,9,16,21].

These changes lead to protein-energy malnutrition, characterized by a loss of body protein and fat deposits and a fall in the serum protein levels. They are more common in children under two years of age and in more severely ill patients and are associated with an increase in mortality and morbidity [27][28][29].

Importance of Nutrition in the Critically Ill Child

One of the fundamental roles of nutrition in the healthy child is to enable growth and development. In contrast, the critically ill child uses nutrients principally to defend the body against disease and, even if a high energy delivery is provided, the body is not able to use this for growth [2]. In these children, nutritional treatment must therefore be orientated to delivering those substrates that favor the maintenance of organ function and recovery from disease [7].

Although nutrition is receiving ever more attention as a part of the treatment of the critically ill child, there are few studies that have systematically analyzed its efficacy [30,31], and recommendations are almost wholly based on expert opinion [2,11,17]. At the present time there are many questions and little evidence regarding the energy delivery and type of nutrients that a critically ill child must receive, the time of starting nutrition, and the most appropriate route for administration and monitoring methods.

A number of studies have analyzed the methods for administering nutrition to the critically ill child. A recent publication reported the results of a survey undertaken in 24 PICUs in 14 Latin-American countries and offers a vision of the way in which nutrition is provided to the critically ill child in Latin-America [32].

It should be noticed the importance of the refeeding syndrome in the critically ill children who can be moved from the starved state to the fed state rapidly via enteral or parenteral nutrition. This syndrome causes severe complications such as electrolyte abnormalities, heart failure, respiratory failure, and death [33].

What Calorie Delivery Does the Critically Ill Child Require?

The critically ill child typically has a lower energy expenditure than the healthy child due to the reduced motor activity and work of breathing, in addition to the sedation, relaxation, and hypothermia; however these patients have different requirements for certain nutrients [2,6]. Only a small percentage of children, those with persistent high fever, trauma, major burns, or prolonged admission to the PICU, have an increased metabolic rate.

The ideal energy delivery that a critically ill child should receive is not known. An insufficient calorie delivery leads to a loss of organ reserves and of the response capacity of the body to aggression. In contrast, an excessive energy delivery can lead to metabolic overload without stimulating anabolism, with increased carbon dioxide production and prolongation of mechanical ventilation.

Numerous formulae have been used to calculate the energy delivery that the critically ill child requires, though none has been found to be useful [6]. Indirect calorimetry, calculated from analysis of the inspired and expired gases, is the best method for evaluating individual energy expenditure [2,6,34]. Although it would be ideal to measure calorimetry continuously, several studies have demonstrated that a measurement over 30 minutes to two hours provides a reliable estimate of daily energy expenditure. However, indirect calorimetry monitors are expensive and complex to use, and their use has not become widespread; furthermore, they are not reliable in children administered an FiO 2 greater than 60%, if there are leaks of greater than 10% from the endotracheal tube, or during extracorporeal membrane oxygenation or venovenous continual renal replacement therapy [2,6,34]. Recently, indirect calorimetry modules have been designed that are adapted to the monitors commonly used in the PICU and that enable its use to be extended. Studies using indirect calorimetry have estimated that the energy expenditure of the critically ill child varies between 40 and 65 Kcal/kg/day and thus, if indirect calorimetry is not available, this is the energy delivery that should be used when starting nutrition [2,6,34].

What Type of Nutrition Should the Critically Ill Child Receive?

For a long time it was thought that severely ill patients could not tolerate enteral nutrition because there would be marked alterations of gastrointestinal motility, digestion, and absorption; parenteral nutrition was therefore considered to be the initial method of feeding.

The principal advantages of parenteral nutrition are that nutrient delivery is independent of the state of the digestive tract, an exact energy delivery can be ensured, and it does not have the risk of digestive tract complications or pulmonary aspiration.

However, numerous studies in the past decade have demonstrated that the majority of critically ill children tolerate enteral nutrition well [2,7,11,16,17,35]. Enteral nutrition is more physiological, has a trophic effect on the intestinal mucosa, and stimulates the intestinal immune system, decreasing bacterial overgrowth and translocation; it therefore reduces the incidence of sepsis and multiorgan failure. Furthermore, enteral nutrition is associated with fewer hepatic and metabolic complications than parenteral nutrition, it is cheaper, it does not require special preparation, and it can be started and modified at any time. At the present time, although very few studies have compared the efficacy and complications of enteral and parenteral nutrition, and although enteral nutrition has not been shown to reduce mortality or length of PICU stay in comparison with parenteral nutrition, the majority of paediatric intensive care physicians consider that enteral nutrition should be the first method for feeding the critically ill child and that it should be started early [2,7,11,16,17,[35][36][37].

Parenteral nutrition should be reserved for those children in whom enteral nutrition is contraindicated or is not tolerated. The contraindications to enteral nutrition have decreased, and now include the following: patients with intestinal obstruction or severe gastrointestinal damage, ischaemia or inflammation; gastrointestinal haemorrhage; peritonitis; and paralytic ileus. In theory, recent gastrointestinal surgery should not be considered a contraindication to enteral nutrition. When it is not possible to achieve an adequate nutrient delivery with enteral nutrition, mixed enteral and parenteral nutrition may be administered [7].

Gastric or Duodeno-Jejunal Nutrition?

The majority of critically ill children receive gastric enteral nutrition as it is more physiological, simpler, and can be started more quickly [31,32]. In many PICUs, gastric nutrition is administered continuously due to the belief that this facilitates tolerance and reduces the volume of gastric residue and, thus, the risk of aspiration. There are no studies that have compared continuous and intermittent gastric administration in critically ill children, although no differences have been found in the incidence of complications in adults.

Gastric nutrition is occasionally poorly tolerated, particularly by children with more serious illness and on mechanical ventilation with deep sedation. This leads to a situation in which a high percentage of critically ill children with gastric nutrition do not receive the prescribed intake.

Transpyloric duodeno-jejunal nutrition, also known as transpyloric post-pyloric enteral nutrition, reduces the volume of gastric residue and the number of interruptions, enabling the nutrition to be increased more rapidly in order to reach the prescribed volume [38,39]. In addition, in the critically ill child and, in particular, in the infant, the introduction of the transpyloric tube is simple and nutrition can therefore be started early. Transpyloric enteral nutrition is well tolerated and has few complications, although it has not been shown to reduce the incidence of pulmonary aspiration [2,7,38,39]. There is only one study in critically ill children that has compared gastric and transpyloric nutrition [30]. Children with transpyloric enteral nutrition reached a higher calorie delivery with the same incidence of complications. In premature neonates, by contrast, transpyloric enteral nutrition has not been shown to have any benefit over gastric feeding and it can increase the incidence of diarrhoea or food intolerance [40].

What Type of Nutrients should the Critically Ill Child Receive?

There are no studies that have analyzed the ideal diet in the critically ill child and there are no new products specifically designed for these patients. For patients of one to two years of age, many authors administer maternal milk or infant formula due to their availability, digestibility, excellent tolerance, and low osmolarity; complete enteral diets are used in older children. An enteral diet for ill infants has recently come onto the market, though studies are necessary to analyze its efficacy in critically ill children and to compare it with infant formula. Nor are there any studies that have demonstrated the advantages of hydrolyzed proteins over complete diets [7].

There is a pronounced increase in catabolism in critically ill patients, which makes it difficult to achieve a positive nitrogen balance. The protein delivery typically recommended in the critically ill child is of 2.5-3 g/kg/day. Some studies have found that a hyperproteic diet increases protein synthesis and improves the nitrogen balance, although it does not reduce catabolism or improve the prognosis [7,21].

The terms immunonutrition and pharmaconutrition have become widespread in recent years. These terms refer to the concept that nutrition serves not only for the administration of energy substrates but also of other substances that are deficient in the critically ill patient and/or that modify the inflammatory and immune responses. Immunomodulating diets supplemented with glutamine, arginine, ribonucleic acid, antioxidants, and omega-3 fatty acids have been used in critically ill adults, with very variable clinical results; some authors have reported a reduction in the incidence of nosocomial infection and even in mortality, whereas others have reported negative effects [41]. Although there are no specific immunomodulating diets for children, one study found a higher incidence of diarrhoea after administering an immunomodulating diet designed for adults to critically ill children [42].

When Should Nutrition be Started?

Critically ill children are particularly vulnerable to the effects of fasting and of prolonged stress, as they have lower percentages of muscle and fat and higher basal energy requirements than adults. A number of studies have demonstrated that the majority of critically ill children tolerate early enteral nutrition well, with no increase in the incidence of complications [2,39]. It would therefore appear reasonable to recommend that critically ill children are not kept fasting for more than 24 to 48 hours. However, many critically ill children start nutrition very late and do not receive the prescribed energy delivery, usually because of the need for fluid restriction, interruptions due to procedures, poor tolerance, or mechanical problems (the tube becomes obstructed or falls out). A recent study found that although 93% of critically ill children received nutrition on the third day after admission, the prescribed energy delivery was only achieved on the fifth day [43].

Characteristics of Parenteral Nutrition

The greatest advances in parenteral nutrition in recent years concern the lipids. The lipid content of parenteral nutrition reduces gluconeogenesis and fat deposition and stimulates lipid oxidation and protein retention. It is interesting that, although many studies have demonstrated the compatibility of lipids with the other substrates of parenteral nutrition, and that combined administration reduces the number of intravenous catheters and manipulations required, reducing the risk of infection, there are still many PICUs that administer lipids separately [32]. New lipid preparations for parenteral nutrition have been developed in recent years, with increased omega-3 and omega-6 fatty acid content based on soya oil, fish oil, and olive oil. These products are metabolized better and have been shown to have anti-inflammatory and immunomodulatory effects. However there are no studies that have analyzed their effects in the critically ill child [7].

A recent retrospective study showed that parenteral nutrition with commercial solutions in critically ill children reduced the cost with respect to preparation of the solutions in the pharmacy department; however, that study did not compare safety, contamination and adverse effects of the preparations [44].

How Should Nutrition be Monitored in the Critically Ill Child

The objectives of monitoring nutrition in the critically ill child must be to evaluate its effect on the nutritional status and to detect adverse effects. Nutritional evaluation in the critically ill child is complicated because, as has been stated above, anthropometric methods (weight and skinfold thickness), which are the simplest, are relatively insensitive to short-term changes and can be affected by variations in body composition (oedema or dehydration). Some serum proteins with a short half-life, such as pre-albumin and retinol binding protein, are relatively sensitive and specific indicators of the nutritional status, although there is still little experience with their use in critically ill children. Indirect calorimetry is the best method for measuring energy expenditure and, together with the nitrogen balance, which is easy to calculate and allows protein catabolism to be determined, and analysis of the nutrition administered, the balance between the delivery and utilization of energy and immediate substrates can be calculated.

The greatest limitation to achieving adequate enteral nutrition in critically ill children is the onset of gastrointestinal complications (38). The most common gastrointestinal complications are abdominal distension, excessive gastric residues, vomiting, diarrhoea, and constipation [31,38]. In one study, the incidence of complications of enteral nutrition was the following: vomiting, 17.9%; abdominal distension, 13.2%; excessive gastric residues, 4.7%; and diarrhoea, 11.3% [31]. In our experience, the incidence of gastrointestinal complications in 526 critically ill children receiving transpyloric enteral nutrition was 11.5%, though definitive withdrawal of the nutrition was required in only 2.1% of patients [38]. The most important risk factors for gastrointestinal complications are shock, acute renal failure, hypophosphataemia, and the administration of catecholamines, sedatives, and muscle relaxants. There are no clinical studies that have evaluated the usefulness of special diets, prokinetics, and laxatives in the prevention and treatment of these complications in the critically ill child.

Conclusions

Malnutrition is very common in the critically ill child and has a negative effect on prognosis, increasing the incidence of complications and the morbidity and mortality. Although scientific evidence is still scarce, it would appear reasonable to start enteral nutrition early in the critically ill child, within the first 24 to 48 hours after admission, when oral feeding is not possible. Energy delivery must be adjusted to energy expenditure and, if this is not possible, a delivery of 40-65 kcal/100calories metabolized/day should be administered, with a protein delivery of 2.5-3 g/kg/day, reaching the prescribed energy delivery within the first 48 to 72 hours. Gastric feeding can be the initial method of nutrition in the majority of critically ill children, keeping transpyloric feeding for more seriously ill patients on mechanical ventilation and who are receiving high doses of sedatives and muscle relaxants, those who have a higher risk of pulmonary aspiration, and those who do not tolerate gastric feeding or in whom an adequate energy delivery cannot be achieved. Parental nutrition should only be used when enteral nutrition is contraindicated or is not tolerated. Frequent monitoring of nutritional and metabolic parameters should be performed, together with vigilance for complications.

The objectives in the future should be to administer individualized nutrition in accordance with the specific characteristics of each critically ill child and to be able to adjust the nutrition continuously according to the metabolic changes and nutritional status. For this, it is important to conduct studies to identify sensitive methods for the evaluation of nutrition that can be applied in the majority of critically ill children. In addition, prospective clinical trials are needed to compare continuous versus intermittent gastric feeding, and to analyze the usefulness of the diet guided by calorimetry and hyperproteic, hydrolyzed, and immunomodulating diets, and the effectiveness of prokinetics and laxatives for the prevention and treatment of the increased incidence of constipation.

Save the Children. Hunger; Save the Children: London, UK. 16Save the Children. Hunger; Save the Children: London, UK, 2011. Available online: http://www.savethechildren.org.uk/en/hunger.htm (accessed on 16 November 2011).

Nutrition therapy in critically ill infants and children. H E Skillman, P E Wischmeyer, JPEN J. Parenter. Enteral. Nutr. 32Skillman, H.E.; Wischmeyer, P.E. Nutrition therapy in critically ill infants and children. JPEN J. Parenter. Enteral. Nutr. 2008, 32, 520-534.

Citokines and metabolic patterns in pediatric patiens with critical illness. G Briassoulis, S Venkatataman, A Thompson, 10.1155/2010/354047Clin. Dev. Inmunol. Briassoulis, G.; Venkatataman, S.; Thompson, A. Citokines and metabolic patterns in pediatric patiens with critical illness. Clin. Dev. Inmunol. 2010, doi: 10.1155/2010/354047.

Valoración del Estado Nutricional en el Paciente Grave. J A Acosta, Acosta, J.A. Valoración del Estado Nutricional en el Paciente Grave;

. Libro Electrónico Medicina Intensiva, 16Madrid, SpainLibro Electrónico Medicina Intensiva: Madrid, Spain, 2008. Available online: http://intensivos.uninet.edu/06/0601.html (accessed on 16 November 2011).

ESPEN guidelines for nutrition screening. J Kondrup, S P Allison, M Elia, B Vellas, M Plauth, Clin. Nutr. 22Kondrup, J.; Allison, S.P.; Elia, M.; Vellas, B.; Plauth, M. ESPEN guidelines for nutrition screening 2002. Clin. Nutr. 2003, 22, 415-421.

Energy expenditure in critically ill children: Correlation with clinical characteristics, caloric intake, and predictive equations. J López-Herce, C Sánchez, S Mencía, M J Santiago, A Carrillo, J M Bellón, An. Pediatr. (Barc. 66López-Herce, J.; Sánchez, C.; Mencía, S.; Santiago, M.J.; Carrillo, A.; Bellón, J.M. Energy expenditure in critically ill children: Correlation with clinical characteristics, caloric intake, and predictive equations. An. Pediatr. (Barc.) 2007, 66, 229-233.

Nutrition in the critically ill child. J López-Herce, An. Pediatr. 71López-Herce, J. Nutrition in the critically ill child. An. Pediatr. (Barc.) 2009, 71, 1-4.

Hospital malnutrition and inflammatory response in critically ill children and adolescents admitted to a tertiary intensive care unit. A F Delgado, T S Okay, C Leone, B Nichols, G M Del-Negro, F A Costa-Vaz, Clinics. 63Delgado, A.F.; Okay, T.S.; Leone, C.; Nichols, B.; Del-Negro, G.M.; Costa-Vaz, F.A. Hospital malnutrition and inflammatory response in critically ill children and adolescents admitted to a tertiary intensive care unit. Clinics 2008, 63, 357-362.

Relationship between energy expenditure, nutritional status and clinical severity before starting enteral nutrition in critically ill children. M Botrán, J López-Herce, S Mencía, J Urbano, M J Solana, A García, A Carrillo, Br. J. Nutr. 105Botrán, M.; López-Herce, J.; Mencía, S.; Urbano, J.; Solana, M.J.; García, A.; Carrillo, A. Relationship between energy expenditure, nutritional status and clinical severity before starting enteral nutrition in critically ill children. Br. J. Nutr. 2011, 105, 731-737.

Energy expenditure and balance following pediatric intensive care unit admission: A longitudinal study of critically ill children. M J Oosterveld, M Van Der Kuip, K De Meer, H J De Greef, R J Gemke, Pediatr. Crit. Care Med. 7Oosterveld, M.J.; Van Der Kuip, M.; De Meer, K.; De Greef, H.J.; Gemke, R.J. Energy expenditure and balance following pediatric intensive care unit admission: A longitudinal study of critically ill children. Pediatr. Crit. Care Med. 2006, 7, 147-153.

Nutrition therapy in a pediatric intensive care unit: Indications, monitoring and complications. P Zamberlan, A F Delgado, C Leone, R Feferbaum, T S Okay, JPEN J. Parenter Enteral. Nutr. 35Zamberlan, P.; Delgado, A.F.; Leone, C.; Feferbaum, R.; Okay, T.S. Nutrition therapy in a pediatric intensive care unit: Indications, monitoring and complications. JPEN J. Parenter Enteral. Nutr. 2011, 35, 523-529.

Malnutrition in hospitalized pediatric patients. K M Hendricks, C Duggan, L Gallagher, A C Carlin, D S Richardson, S B Collier, W Simpson, C Lo, Arch. Pediatr. Adolesc. Med. 149Hendricks, K.M.; Duggan, C.; Gallagher, L.; Carlin, A.C.; Richardson, D.S.; Collier, S.B.; Simpson, W.; Lo, C. Malnutrition in hospitalized pediatric patients. Arch. Pediatr. Adolesc. Med. 1995, 149, 1118-1122.

Malnutrition in critically ill children: From admission to 6 month after discharge. J Hulst, K Joosten, L Zimmermann, W Hop, S Van Buuren, H Büller, D Tibboel, J Van Goudoever, Clin. Nutr. 23Hulst, J.; Joosten, K.; Zimmermann, L.; Hop, W.; van Buuren, S.; Büller, H.; Tibboel, D.; van Goudoever, J. Malnutrition in critically ill children: From admission to 6 month after discharge. Clin. Nutr. 2004, 23, 223-232.

Nutritional deficiencies during critical illness. N M Mehta, C P Duggan, Pediatr. Clin. North Am. 56Mehta, N.M.; Duggan, C.P. Nutritional deficiencies during critical illness. Pediatr. Clin. North Am. 2009, 56, 1143-1160.

Nutritional assessment in the critically ill child. Curr. G Briassoulis, Pediatr. Rev. 2Briassoulis, G. Nutritional assessment in the critically ill child. Curr. Pediatr. Rev. 2006, 2, 233-243.

The effect of enteral nutrition on nutritional status in the critically ill child. C Sánchez, J López-Herce, C García, M Rupérez, E García, Clin. Intensive Care. 16Sánchez, C.; López-Herce, J.; García, C.; Rupérez, M.; García, E. The effect of enteral nutrition on nutritional status in the critically ill child. Clin. Intensive Care 2005, 16, 75-78.

ASPEN Board of directors. ASPEN clinical guidelines: Nutrition support of the critically ill child. N M Mehta, C Compher, JPEN J. Parenter Enteral. Nutr. 33Mehta, N.M.; Compher, C.; ASPEN Board of directors. ASPEN clinical guidelines: Nutrition support of the critically ill child. JPEN J. Parenter Enteral. Nutr. 2009, 33, 260-276.

Effect of critical illness and nutritional support on mucosal mass and function. T M Lara, D O Jacobs, Clin. Nutr. 17Lara, T.M.; Jacobs, D.O. Effect of critical illness and nutritional support on mucosal mass and function. Clin. Nutr. 1998, 17, 99-105.

. J Fleta, A Sarriá, M Bueno-Lozano, Perez-Choliz, An. Esp. Pediatr. 29Fleta, J.; Sarriá, A.; Bueno-Lozano, M.; Perez-Choliz, V. Nutritional obesity. An. Esp. Pediatr. 1988, 29, 7-12.

Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations. J M L De Vree, J A Romijn, K S Mok, L M Mathus-Vliegen, C P Stoutenbeek, J D Ostrow, G N Tytgat, H P Sauerwein, R P Oude Elferink, A K Groen, Am. J. Clin. Nutr. 70De Vree, J.M.L.; Romijn, J.A.; Mok, K.S.; Mathus-Vliegen, L.M.; Stoutenbeek, C.P.; Ostrow, J.D.; Tytgat, G.N.; Sauerwein, H.P.; Oude Elferink, R.P.; Groen, A.K. Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations. Am. J. Clin. Nutr. 1999, 70, 70-77.

Enteral nutrition in the critically ill child: Comparison of standard and protein-enrich diets. M Botrán, J López-Herce, S Mencía, J Urbano, M J Solana, A García-Figueruelo, J. Pediatr. 159Botrán. M.; López-Herce, J.; Mencía, S.; Urbano, J.; Solana, M.J.; García-Figueruelo, A. Enteral nutrition in the critically ill child: Comparison of standard and protein-enrich diets. J. Pediatr. 2011, 159, 27-32.

Nutritional assessment and related biochemical changes in the critically ill child. M Tamiolaki, J Maropoulos, J Papadatos, Intensive Care Med. Suppl 1, S39Tamiolaki, M.; Maropoulos, J.; Papadatos, J. Nutritional assessment and related biochemical changes in the critically ill child. Intensive Care Med. 1995, Suppl 1, S39.

Influence of an aggressive early enteral nutrition protocol on nitrogen balance in critically ill children. G Briassoulis, A Tsorva, N Zavras, T Hatzis, J. Nutr. Biochem. 13Briassoulis, G.; Tsorva, A.; Zavras, N.; Hatzis, T. Influence of an aggressive early enteral nutrition protocol on nitrogen balance in critically ill children. J. Nutr. Biochem. 2002, 13, 560-569.

Metabolic changes in critically ill children. P Ruiz, C Aparicio, J López-Herce, M Martínez, L Sancho, An. Esp. Pediatr. 51Ruiz, P.; Aparicio, C.; López-Herce, J.; Martínez, M.; Sancho, L. Metabolic changes in critically ill children. An. Esp. Pediatr. 1999, 51, 143-148.

Comparison of serum fibronectin, prealbumin and albumin concentrations during nutritional repletion in protein-calorie malnourish infants. M C Yoder, D C Anderson, G S Gopalakrishna, S D Douglas, R A Polin, J. Pediatr. Gastroenterol. Nutr. 6Yoder, M.C.; Anderson, D.C.; Gopalakrishna, G.S.; Douglas, S.D.; Polin, R.A. Comparison of serum fibronectin, prealbumin and albumin concentrations during nutritional repletion in protein-calorie malnourish infants. J. Pediatr. Gastroenterol. Nutr. 1987, 6, 84-88.

Assessing the efficacy of intravenous nutrition in general surgical patients-dynamic nutritional assessment using plasma proteins. J M Church, G L Hill, JPEN J. Parenter Enteral. Nutr. 11Church, J.M.; Hill, G.L. Assessing the efficacy of intravenous nutrition in general surgical patients-dynamic nutritional assessment using plasma proteins. JPEN J. Parenter Enteral. Nutr. 1987, 11, 135-140.

Malnutrition nutritional indices, and early enteral feeding in critically ill children. G Briassoulis, N Zavras, T Hatzis, Nutrition. 17Briassoulis, G.; Zavras, N.; Hatzis, T. Malnutrition nutritional indices, and early enteral feeding in critically ill children. Nutrition 2001, 17, 548-557.

Nutritional depletion in critically ill children: Association with physiologic instability and increase quantity of care. M M Pollack, U E Ruttimann, J S Wiley, JPEN J. Parenter Enteral. Nutr. 9Pollack, M.M.; Ruttimann, U.E.; Wiley, J.S. Nutritional depletion in critically ill children: Association with physiologic instability and increase quantity of care. JPEN J. Parenter Enteral. Nutr. 1985, 9, 309-313.

Malnutrition as an independent predictor of clinical outcomes in critically ill children. F D Menezes, H P Leite, P C Nogueira, 10.1016/j.nut.2011.05.015Nutrition. Menezes, F.D.; Leite, H.P.; Nogueira, P.C. Malnutrition as an independent predictor of clinical outcomes in critically ill children. Nutrition 2011, doi:10.1016/j.nut.2011.05.015.

Gastric vs. small-bowel feeding in critically ill children receiving mechanical ventilation: A randomized controlled trial. K L Meert, K M Daphtary, N A Metheny, Chest. 126Meert, K.L.; Daphtary, K.M.; Metheny, N.A. Gastric vs. small-bowel feeding in critically ill children receiving mechanical ventilation: A randomized controlled trial. Chest 2004, 126, 872-878.

Grupo de Trabajo de Nutrición de la Sociedad Española de Cuidados Intensivos Pediátricos. Artificial nutrition in the pediatric intensive care units. J L Pérez-Navero, P Dorao, López-Herce, J Cid, I De La Rosa, M Pujol, M T Hermana, An. Pediatr. (Barc. 62Pérez-Navero, J.L.; Dorao, P.; López-Herce, Cid, J.; de la Rosa, I.; Pujol, M.; Hermana, M.T. Grupo de Trabajo de Nutrición de la Sociedad Española de Cuidados Intensivos Pediátricos. Artificial nutrition in the pediatric intensive care units. An. Pediatr. (Barc.) 2005, 62, 105-112.

The Latin-American survey on nutrition in pediatric intensive care (ELAN-CIP). S Campos, J S Sasbón, An. Pediatr. 71Campos, S.; Sasbón, J.S. The Latin-American survey on nutrition in pediatric intensive care (ELAN-CIP). An. Pediatr. (Barc.) 2009, 71, 5-12.

Refeeding in the ICU: An adult and pediatric problem. M C Byrnes, J Stangenes, Curr. Opin. Clin. Nutr. Metab. Care. 14Byrnes, M.C.; Stangenes, J. Refeeding in the ICU: An adult and pediatric problem. Curr. Opin. Clin. Nutr. Metab. Care 2011, 14, 186-192.

Evaluation of energy expenditure in children. Physiological and clinical implications and measurement methods. A Sancho, P Dorao, F Ruza, An. Pediatr. (Barc. 68Sancho, A.; Dorao, P.; Ruza, F. Evaluation of energy expenditure in children. Physiological and clinical implications and measurement methods. An. Pediatr. (Barc.) 2008, 68, 165-180.

The use of transpyloric enteral nutrition in the critically ill child. C Sánchez, J López-Herce, M Moreno De Guerra, J. Intensive Care Med. 15Sánchez, C.; López-Herce, J.; Moreno de Guerra, M. The use of transpyloric enteral nutrition in the critically ill child. J. Intensive Care Med. 2000, 15, 247-254.

Transpyloric enteral nutrition in critically ill children (I) Technics and indications. C Sánchez, J López-Herce, A Carrillo, A Bustinza, Z L Sancho, D Vigil, An. Pediatr. (Barc. 59Sánchez, C.; López-Herce, J.; Carrillo, A.; Bustinza, A.; Sancho, Z.L.; Vigil, D. Transpyloric enteral nutrition in critically ill children (I) Technics and indications. An. Pediatr. (Barc.) 2003, 59, 19-24.

Early enteral nutrition in acutely ill patients. A systemic review. P E Marik, G P Zaloga, Crit. Care Med. 29Marik, P.E.; Zaloga, G.P. Early enteral nutrition in acutely ill patients. A systemic review. Crit. Care Med. 2001, 29, 2264-2270.

Risk factors for gastrointestinal complications in critically ill children with transpyloric enteral nutrition. J López-Herce, M J Santiago, C Sánchez, S Mencía, A Carrillo, D Vigil, Eur. J. Clin. Nutr. 62López-Herce, J.; Santiago, M.J.; Sánchez, C.; Mencía, S.; Carrillo, A.; Vigil, D. Risk factors for gastrointestinal complications in critically ill children with transpyloric enteral nutrition. Eur. J. Clin. Nutr. 2008, 62, 395-400.

Early transpyloric enteral nutrition in critically ill children. C Sánchez, J López-Herce, A Carrillo, S Mencía, D Vigil, Nutrition. 23Sánchez, C.; López-Herce, J.; Carrillo, A.; Mencía, S.; Vigil, D. Early transpyloric enteral nutrition in critically ill children. Nutrition 2007, 23, 16-22.

Transpyloric versus gastric tube feeding for preterm infants. W Mcguire, P Mcewan, Cocharne Database Syst. Rev. 330McGuire, W.; McEwan, P. Transpyloric versus gastric tube feeding for preterm infants. Cocharne Database Syst. Rev. 2007, 3, CD003487:1-CD003487:30.

Pharmaconutrition: A new emerging paradigm. N E Jones, D K Heyland, Curr. Opin. Gastroenterol. 24Jones, N.E.; Heyland, D.K. Pharmaconutrition: A new emerging paradigm. Curr. Opin. Gastroenterol. 2008, 24, 215-222.

Early enteral administration of immunonutrition in critically ill children: Results of a blinded randomized controlled clinical trial. G Briassoulis, O Filippou, E Hatzi, I Papassotiriou, T Hatzis, Nutrition. 21Briassoulis, G.; Filippou, O.; Hatzi, E.; Papassotiriou, I.; Hatzis, T. Early enteral administration of immunonutrition in critically ill children: Results of a blinded randomized controlled clinical trial. Nutrition 2005, 21, 799-807.

Nutritional goals, prescription and delivery in a pediatric intensive care unit. M De Neef, V G M Geukers, A Dral, R Lindeboom, H P Sauerwein, A P Bos, Clin. Nutr. 27de Neef, M.; Geukers, V.G.M.; Dral, A.; Lindeboom, R.; Sauerwein, H.P.; Bos, A.P. Nutritional goals, prescription and delivery in a pediatric intensive care unit. Clin. Nutr. 2008, 27, 65-71.

Cost analysis of two approaches to parenteral nutrition in critically ill children. T Gamsjäger, L Brenner, E Schaden, C Sitzwohl, C Weinstabl, Pediatr. Crit. Care Med. 10Gamsjäger, T.; Brenner, L.; Schaden, E.; Sitzwohl, C.; Weinstabl, C. Cost analysis of two approaches to parenteral nutrition in critically ill children. Pediatr. Crit. Care Med. 2009, 10, 163-165.

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The BraveNet prospective observational study on integrative medicine treatment approaches for pain

Donald I Abrams
Rowena Dolor
Rhonda Roberts
Constance Pechura
Jeffery Dusek
Sandi Amoils
Steven Amoils
Kevin Barrows
Joel S Edman
Joyce Frye
Erminia Guarneri
Ben Kligler
Daniel Monti
Myles Spar
Ruth Q Wolever
The BraveNet prospective observational study on integrative medicine treatment approaches for pain
R E S E A R C H A R T I C L E Open Access
Background: Chronic pain affects nearly 116 million American adults at an estimated cost of up to $635 billion annually and is the No. 1 condition for which patients seek care at integrative medicine clinics. In our Study on Integrative Medicine Treatment Approaches for Pain (SIMTAP), we observed the impact of an integrative approach on chronic pain and a number of other related patient-reported outcome measures.Methods: Our prospective, non-randomized, open-label observational evaluation was conducted over six months, at nine clinical sites. Participants received a non-standardized, personalized, multimodal approach to chronic pain. Validated instruments for pain (severity and interference levels), quality of life, mood, stress, sleep, fatigue, sense of control, overall well-being, and work productivity were completed at baseline and at six, 12, and 24 weeks. Blood was collected at baseline and week 12 for analysis of high-sensitivity C-reactive protein and 25-hydroxyvitamin D levels. Repeated-measures analysis was performed on data to assess change from baseline at 24 weeks.Results: Of 409 participants initially enrolled, 252 completed all follow-up visits during the 6 month evaluation. Participants were predominantly white (81%) and female (73%), with a mean age of 49.1 years (15.44) and an average of 8.0 (9.26) years of chronic pain. At baseline, 52% of patients reported symptoms consistent with depression. At 24 weeks, significantly decreased pain severity (−23%) and interference (−28%) were seen. Significant improvements in mood, stress, quality of life, fatigue, sleep and well-being were also observed. Mean 25-hydroxyvitamin D levels increased from 33.4 (17.05) ng/mL at baseline to 39.6 (16.68) ng/mL at week 12.Conclusions: Among participants completing an integrative medicine program for chronic pain, significant improvements were seen in pain as well as other relevant patient-reported outcome measures.Trial Registration: ClinicalTrials.gov, NCT01186341

Musculoskeletal disorders

Background A 2011 Institute of Medicine report, Relieving Pain in America, estimates that chronic pain affects nearly 116 million American adults, a staggering number that surpasses those affected by heart disease, cancer, and diabetes combined [1]. The report concludes that chronic pain costs between $560 billion and $635 billion annually in medical expenses and lost productivity. Although there have been some therapeutic advances, many patients with chronic pain become resistant to conventional medical treatments or suffer adverse effects from widely used prescription medications with high addictive potential, such as non-steroidal anti-inflammatory agents or opiates. For these reasons, patients with chronic pain frequently seek to integrate complementary therapies, often without the knowledge of their primary care provider [2][3][4].

Integrative medicine provides patient-centered care and addresses the full range of physical, emotional, mental, social, spiritual, and environmental influences that affect a person's health [5]. Employing a personalized strategy that considers the patient's unique conditions, needs, and circumstances, integrative medicine uses the most appropriate interventions from an array of scientific disciplines to heal illness and help people regain and maintain optimum health. Because integrative medicine is a "whole systems" approach that employs multiple modalities in concert as opposed to an isolated complementary therapy, studying outcomes is more challenging than evaluating an isolated pharmaceutical or botanical intervention. Chronic pain is one of the main reasons patients seek care at integrative medicine clinics [6,7].

In an effort to capture data on patient-reported outcomes in integrative medicine, a number of leading integrative medicine clinics have collaborated to form the first practice-based research network in the field: the Bravewell Integrative Medicine Research Network (BraveNet). BraveNet's initial project was to characterize 4182 patients seeking care at nine clinical sites in a systematic fashion by collecting information at a single time point [6]. This repository of data confirmed the high utilization of integrative medicine by chronic pain patients and informed the present Study on Integrative Medicine Treatment Approaches for Pain (SIMTAP). We report the impact of a six-month integrative approach on chronic pain and a number of other related patient-reported outcome measures.

Methods

Design overview

Using a prospective, non-randomized, open-label observational design, we assessed patients at baseline and six-, 12-, and 24-week visits. At baseline, participants completed a demographic questionnaire as well as the instruments utilized to assess outcomes over the duration of the study. Within a week of each projected follow-up data collection visit, participants were asked to complete the battery of questionnaires collected at baseline. Information on integrative interventions, prescription medications, and vitamins and supplements utilized was collected at each study visit. Questions about integrative modalities being utilized were answered at weeks six, 12, and 24 to define the scope of the interventions received.

Setting and participants

Eligible patients were enrolled at each of the nine BraveNet clinical sites. Participants were clinic patients aged 18 or older who were seeking their initial treatment at the center for chronic pain, defined as persisting for at least the past three months with an average level over the past month of at least 4 of 10 on a numerical rating scale. Participants provided written informed consent before initiation of any study-related procedures.

Intervention

In keeping with the integrative medicine philosophy of individualized patient-centered care, no standardized prespecified clinical intervention for chronic pain was prescribed for all study participants. Instead, practitioners at each of the network sites devised treatment plans for participating chronic pain patients. All BraveNet sites include integrative physicians, acupuncturists, mindfulness instructors, and yoga instructors; some also incorporate massage therapists, manual medicine therapists, fitness/ movement specialists, dietician/nutritionists, psychologists, healing touch therapists, and other energy practitioners.

Outcomes and follow-up

The battery of validated outcome measurements collected at each visit included the Brief Pain Inventory (BPI) [8], the 12-Item Short Form Health Survey (SF-12v2) [9], the Center for Epidemiologic Studies Depression Scale (CES-D) [10], the Perceived Stress Scale-4 (PSS-4) [11], the Arizona Integrative Outcomes Scale (AIOS) [12], and the Work Productivity and Activity Impairment (WPAI) survey [13]. In addition, numerical rating scales were utilized to assess fatigue, restfulness of sleep, and sense of control. Venipuncture for determination of high-sensitivity C-reactive protein (hs-CRP) (a marker of inflammation) and 25-hydroxyvitamin D levels (potentially associated with pain syndromes) was performed at baseline and week 12.

Statistical analysis

An objective of this network study was to demonstrate that the sites could enroll and follow patients over a 24-week period and collect serial laboratory specimens. For this analysis, we focus on those participants who completed the entire 24-week program. A post hoc sensitivity analysis was performed to determine potential differences between enrolled patients completing all four study visits ("completers") and those who completed at least the baseline visit but not the entire study ("noncompleters"). Comparisons of baseline characteristics were assessed utilizing t-tests for continuous variables and chi-square tests for categorical measures.

Descriptive statistics were summarized using frequencies (percentages) for categorical variables. Means, standard deviations, medians, quartiles, minimums, and maximums were reported for all continuous variables.

Pain and quality-of-life scales

Repeated-measures analyses of variance were performed on study completers to detect changes in BPI subscales-Pain Severity and Interference-over time as well as changes in quality-of-life scores. Results are summarized with a point estimate of mean change in the outcome measures between baseline and any specified follow-up visit with 95% confidence intervals. P values are reported for overall model summary, indicating any difference between any two given points between baseline and 24 weeks. If the P value was significant (<.05), follow-up linear regression analyses were done to verify that the trends were consistent in direction throughout all study visits, indicating constant improvement or decline from visit to visit.

A secondary sensitivity analysis was done to determine the impact of including only study completers for the primary outcome-BPI Pain Severity and Interference scores-instead of using the more conservative method of last observation carried forward. The repeated-measures analysis for the BPI Pain Severity and Interference scores was run on three subgroups of the sample assuming that values at missed visits were carried forward from the last nonmissing study visit: (1) all enrolled patients, (2) patients completing at least one postbaseline study visit, and (3) patients completing all follow-up study visits.

Multivariate logistic regression analysis was performed to look at variables that influenced the pain response. Responders were defined as those with at least a 20% decrease in the BPI interference score over 24 weeks. Variables included in the model were age, gender, ethnicity (Hispanic or non-Hispanic), years with chronic pain, body mass index, and baseline values for the BPI interference score, SF-12 physical component score, SF-12 mental component score, CES-D score, and PSS-4.

Lab measures (hs-CRP and Vitamin D)

We used dependent t-tests to determine whether the 12week study visit laboratory measures differed significantly when compared to baseline values. A P value of < .05 was considered to indicate statistical significance.

Results

A total of 409 participants were consented and enrolled at the nine BraveNet sites between June 2009 and November 2010. The number of participants contributing baseline data per site ranged from 22 to 65 (median: 49). Of the participants, 252 completed all study assessments during the 24-week study and are the basis of our primary analysis. Table 1 provides baseline demographics of the study completers compared with those who did not contribute data at the 24-week visit. Regardless of completion status, the majority of the participants were women, on average nearly 50 years of age and slightly overweight, who reported experiencing pain for about nine years (completers) or seven years (noncompleters). Other than the duration of pain, completers and noncompleters were similar in demographics and baseline scores on all patient-reported outcomes measured. Subsequent results are presented for the completers only.

Fifty-one percent of the participants reported pain in the neck, 49% lumbar spine, 46% shoulder, 37% hip, 36% knee, 32% sacrum, 31% head, 26% leg, 25% buttock, 25% thoracic spine, and 23% foot. Multiple sites could be selected.

At week 24, participants were receiving a wide range of modalities in their prescribed integrative suite of therapies (see Table 2). Figure 1 is a mosaic plot of the modalities utilized over the course of the study. The highest number of patients received 4 modalities (N = 55), including acupuncture/Chinese medicine (51.9%), manipulation therapy (17.3%), mind/body techniques (7.7%), integrative medicine consult (7.7%), exercise (7.7%), yoga (1.9%), and alternative medical systems therapy (5.8%). Overall, acupuncture/Chinese medicine, manipulation therapy, and mind/body therapy were the most commonly received modalities.

Current pain medications reported at week 24 included ibuprofen (45%), acetaminophen (32%), naproxen (20%), triptans (18%), hydrocodone (13%), aspirin (11%), and oxycodone (10%). Medication use was unchanged from baseline. Dietary supplements used by more than 10% of participants at week 24 included vitamin D (81%), fish oil (65%), magnesium (32%), green tea (24%), glucosamine (19%), and turmeric (13%). The only changes from baseline in proportion of patients using supplements were seen in vitamin D, magnesium, and glucosamine (55%, 27%, and 26% at baseline, respectively). The mean monthly cost of supplements increased from $47 at baseline to $72 at week 24.

Pain scores

The BPI is composed of four items that assess pain severity and an additional seven questions that assess how the pain interferes with life [8]. The composite score summarizes the patient pain experience over the past 24 hours, with 1-4 rated as mild, 5-6 moderate, and 7-10 severe. The mean baseline severity and interference scores in our cohort were 4.7 (1.86) and 4.7 (2.53), respectively. The overall model results for all three subgroups in both BPI severity and BPI interference scales were statistically significant (P < .001). Additionally, mean change scores between baseline and any specific post-baseline study visit for both BPI scales were significantly decreased (P < .001). Figure 2 portrays the change in BPI scores over the study duration. Mean severity scores decreased 23% from moderate to mild at 24 weeks. Interference scores dropped 28% to a mean of 3.3 at week 24.

Depression, stress, and quality of life

Fifty-two percent of completers scored 16 or greater on the CES-D at baseline, consistent with symptoms of depression. As seen in Table 3, by week 24 the mean score had dropped from 17.9 to 13.8 (median score decreased from 16.0 to 11.0); at week 24, only 35% had scores consistent with depressive symptoms. Although both the mental and physical component scores on the SF-12v2 remained below the U.S. norm of 50 at week 24, the mean mental component score rose from 43.5 at baseline to 46.5, and the mean physical component score rose from 37.7 at baseline to 41.5 at week 24 (P < .001). Similarly, stress and fatigue decreased over time, and the participants' sense of control increased (all P < .001).

The AIOS asks participants to summarize their sense of well-being for the entire month by marking a point on a plain line with an "X" somewhere between "Worst you have ever been" and "Best you have ever been." Participants' sense of well-being increased significantly from a baseline mean of 41.7 to 55.9 at week 24 (P < .001). To put these values in context, rehabilitation center patients scored an average of 33 and healthy controls a 61 on the AIOS [12].

Work productivity

The WPAI survey assesses the impact of an intervention with respect to daily activity and productivity [13]. It has been previously validated that overall work productivity is significantly related to general health perceptions. The WPAI survey was completed by the 145 participants who reported having employment. The results (see Table 4) demonstrate improvement in all parameters over the 24-week study period.

Laboratory studies

Specimens for hs-CRP and 25-hydroxyvitamin D were obtained at baseline and at week 12. Mean hs-CRP decreased from 4.0 (10.21) mg/L at baseline to 2.7 (6.55) mg/L at 12 weeks.

The mean 25-hydroxyvitamin D level at baseline was 33.4 (17.05) ng/mL. At week 12, the mean value had increased to 39.6 (16.68) ng/mL (P < .001). Considering >30 ng/mL as the desirable range for 25-hydroxyvitamin D, 52% of the participants were in the desirable range at baseline, and 70% were at week 12 [14].

Predictors of response

A multivariate logistic regression analysis showed that patients with fewer years of chronic pain (p = 0.03), non-Hispanic populations (p = 0.04), and those with higher (worse) baseline BPI interference scores (p = 0.002) and SF-12 physical component scores (p = 0.008) were more likely to have a clinical meaningful response (i.e. ≥ 20 decrease in the BPI interference score over 24 weeks). Age, gender, BMI, baseline SF-12 mental component score, CES-D score, and PSS-4 score were not significant predictors of response.

Discussion and conclusion

The initial project of the BraveNet practice-based research network involved collection of a one-time questionnaire from about 500 participants at each of our nine clinical sites [6]. Building on the initial experience of collecting data as a multi-site group, SIMTAP demonstrated our ability to enroll participants and capture outcomes in a prospective longitudinal study, requiring serial follow-up data collection at three time points beyond baseline as well as the ability to collect and process laboratory specimens. The establishment of this functioning practice-based research network in integrative medicine is one of the main accomplishments of this endeavor. We surpassed the target enrollment of 400, with 409 participants ultimately enrolled. Of these, 88 (21.5%) did not contribute data at the six-week study visit. At 24 weeks, 66% of the enrolled participants were available for follow-up. Chronic pain trials frequently encounter retention issues for a number of reasons, including the nature of the population. It has been suggested that in a typical 12-week, fixed-dose, placebo-controlled trial, a dropout rate of 20%-50% is to be expected [15]. Our participants received no financial incentives for their participation in the 24-week study and, in fact, were responsible for the cost of their integrative treatments. A recent trial on a three-month yoga intervention versus usual care for chronic back pain randomized 156 patients to the yoga arm [16]. Of these, 93 (60%) attended at least three of the first six sessions and at least three others. Acknowledging the need to improve retention, we conclude that within the context of chronic pain intervention trials, the practice-based research network is successful in recruiting and retaining patients who contribute data to assess the impact of the interventions on patient-reported outcomes of interest in a usual care (non-efficacy) setting.

Our study demonstrates that an integrative approach to treating chronic pain had a significant impact on patients' pain as well as on associated symptoms and quality of life. This success was in the context of long-standing chronic pain, with an average duration in our sample of greater than eight years. Whereas conventional medical interventions, such as pharmaceuticals or surgery, generally focus on one outcome, integrative interventions have the potential to affect multiple aspects of health and well-being [17]. It has been recommended that additional patientrecorded outcome measures are also important to monitor, particularly in studies of chronic pain [18]. The trends in decreased pain, stress, depression, and fatigue, and improvement in physical quality of life and overall well-being, were consistent over the 24-week duration of the trial and suggest the possibility of sustainable effects of the integrative interventions [19]. Particularly notable is the decrease Figure 2 Repeated-measures analysis of primary outcome: Brief Pain Inventory (BPI) pain scores. Reported P values are overall model results summarizing any potential change across four time points throughout the study. Individual estimated change from baseline scores specify changes in scores from baseline to any designated study visit on a scale from 0 to 10, with 0 indicating least possible pain or interference. in severity of participants' depression symptoms, given what is known about the challenges of treating chronic pain and depression. In addition, findings on the WPAI survey suggest that the improvements measured in patient-reported outcomes also translated into greater productivity at work. Predictors of response to an integrative medicine approach included years of chronic pain, ethnicity, and baseline BPI interference and SF-12 physical component scores.

We investigated hs-CRP as a general marker of inflammation rather than as a predictor of cardiac risk [20,21]. The mean hs-CRP value declined one point, suggesting a trend toward decreased inflammation. In a previous study on musculoskeletal pain conducted at our Minneapolis BraveNet site, 93% of the participants were found to have insufficient levels of 25-hydroxyvitamin D (≤20 ng/mL) [22]. To further assess the relationship of hypovitaminosis D to pain, we included vitamin D levels in SIMTAP. Our patients presented with baseline vitamin D levels higher than those seen in the prior study and in the average American adult [21,23]. This likely reflects awareness among both patients and practitioners of the increasing importance of adequate vitamin D levels. The findings that 70% of SIMTAP participants had values greater than 30 ng/mL and none were deficient at week 12 reflect the serious attention paid to maintaining sufficient vitamin D in integrative medicine practices.

Limitations

One limitation of this study is the loss to follow-up. Our results describe the outcomes of 252 participants at nine sites who completed all study visits during the 24-week integrative medicine intervention for chronic pain. It could be argued that these completers were somehow different from the noncompleters, skewing the final study results, although this notion is not supported by the sensitivity analysis. The bulk of patients lost failed to return for the first study follow-up at week six. This may represent patients who were "shopping" for a new approach for their chronic pain, visited one of the centers, enrolled in SIMTAP, and then chose not to return for follow-up care. The 252 completers can be considered as being treated "on protocol" for analysis in this prospective non-randomized open-label intervention.

A second limitation is the absence of a control group. It could be argued that the significant benefits we observed in SIMTAP participants may have nothing to do with the integrative intervention per se. Because we did not control for natural history and the passage of time, we cannot estimate what proportion of the observed benefits would have occurred separately from the intervention themselves. Without a control group of equal attention, it could be argued that the benefits observed were related to the degree of attention participants received at our centers. Because one of our goals was to assist in the development of our practice-based research network and to demonstrate that we could recruit, follow, and retain participants, as well as collect and process laboratory specimens, we opted not to include randomization or comparison to a control group in our design.

In the spirit of the individualized care that characterizes the integrative medicine approach to the unique individual, we did not mandate a standardized intervention for all SIMTAP participants. Although this makes it more difficult to define the precise treatment that patients received, the network felt that the personalized treatment plan was preferred. Practitioners of traditional Chinese medicine generally devise individualized treatment plans based on each patient's unique diagnosis rather than follow a standard intervention based on the complaint. In a seminal randomized controlled trial of Chinese herbal medicine for treatment of irritable bowel syndrome, investigators compared a standard and an individualized Chinese herbal formulation to a placebo [24]. Results showed that compared with patients in the placebo group, patients in the two active treatment groups had improvements in bowel symptoms as rated by both the patients and their gastroenterologists at the end of the 16-week intervention. However, at follow-up 14 weeks after completion of the treatment, only the individualized herbal medicine treatment group maintained improvement.

Future directions

The results of SIMTAP suggest that the tailored, multimodal approach to treating chronic pain combining conventional and complementary therapies improves quality of life and reduces pain, stress and depressive symptoms. The components of integrative medicine that contribute to improving patients' physical and emotional health require further research since this study is not powered to compare the effectiveness of different combinations to each other. In addition, a comparison of integrative medicine to usual care would help define the effectiveness of different treatment approaches to chronic pain. Investigating the therapeutic impact of a "whole systems" approach such as our integrative intervention is a daunting challenge, as funding agencies are accustomed to a more reductionist approach to assessing which individual component of a multimodality intervention is the active one. In addition, the conventional approach would be to deliver a standardized intervention to all study participants. These conventions run counter to the philosophy of integrative medicine, which places the needs of the unique person seeking care first and designs an appropriate personalized intervention based on the individual's assessment, much akin to practitioners of traditional Eastern medicine. New initiatives, such as the Patient Reported Outcome Measurement Information System and the Patient-Centered Outcomes Research Institute, will hopefully have an impact in advancing research of integrative medicine interventions [25][26][27][28].

The 2010 Patient Protection and Affordable Care Act required the Department of Health and Human Services to enlist the Institute of Medicine in examining pain as a public health problem. The recommendations from the institute suggest that among the "steps to improving care, healthcare providers should increasingly aim at tailoring pain care to each person's experience, and self-management of pain should be promoted" [1]. Although it is often easier and faster to respond to the patient presenting with chronic pain by writing a prescription, increasingly for a substance with addictive potential, an integrative medicine approach may more closely approximate the Institute of Medicine's blueprint for transforming health care.

Figure 1
1Mosaic plot of Modalities received by Patients. The x-axis shows the number of modalities received and the width of the column is proportional to the number of patients in each category -1 modality (n = 22 patients), 2 modalities (n = 50), 3 modalities (n = 50), 4 modalities (n = 52), 5 modalities (n = 42), 6 modalities (n = 19), 7 modalities (n = 5), all 8 modalities (n = 3). The y-axis shows the proportion of patients who received each modality; the actual percentages are included in each colored box (where feasible).

The protocol was approved by the Institutional Review Board at each participating site including Allina Health Institutional Review Board; Beth Israel Medical Center Human Subjects Protection Office Institutional Review Board; Duke University Health Systems Institutional Review Board; The Scripps Clinic Institutional Review Board; Thomas Jefferson University Division of Human Subjects Protection; University of California Los Angeles Institutional Review Board; University of California San Francisco Committee on Human Research; and University of Maryland Institutional Review Board.

Table 1
1Baseline measures: completers versus noncompleters a BMI body mass index, BPI Brief Pain Inventory, CES-D Center for Epidemiologic Studies Depression Scale, PSS-4 Perceived Stress Scale-4, SF-12v2 12-Item Short Form Health Survey. Values shown are means (SD).P value indicates significant difference between groups if < .05.Measure
Completers
(N = 252)

Noncompleters
(N = 157)

P Value b

Age, y
48.6 (15.18)
49.8 (15.89)
.44

Female
74.1%
71.1%
.57

BMI (kg/m 2 )
25.8 (5.49)
25.9 (6.42)
.81

Duration of pain, y
8.6 (9.34)
6.9 (9.04)
.06

CES-D (0 c -60)
17.9 (10.49)
18.3 (10.46)
.71

PSS-4 (0 c -16)
6.7 (3.14)
6.4 (3.17)
.37

SF-12v2 mental (0-100 c )
43.5 (10.43)
44.3 (11.17)
.47

SF-12v2 physical (0-100 c )
37.7 (10.24)
36.8 (10.82)
.40

BPI Severity (0 c -10)
4.6 (1.86)
4.9 (1.86)
.11

BPI Interference (0 c -10)
4.6 (2.58)
4.7 (2.47)
.67

a

b

c

Indicates better health.

Table 2
2Current integrative medicine pain treatments at 24 weeks for completers (N = 252)Integrative modality group a
Patients
Percentage

Acupuncture/TCM
115
47.3%

Manipulation Therapy
51
21.0%

Mind/Body
27
11.1%

Integrative Medicine Consult
25
10.3%

Exercise
12
4.9%

Yoga
6
2.5%

Alternative Medical Systems
6
2.5%

Energy Therapy
1
0.4%

a Individual integrative medicine modalities were grouped into eight
categories. Acupuncture/TCM: acupuncture, traditional Chinese medicine,
tai chi; Manipulation therapy: chiropractic, osteopathy, massage; Mind/Body:
biofeedback, deep breathing exercises, hypnosis, meditation, prayer for health,
progressive relaxation, psychotherapy; Alternative Medicine Systems:
Ayurveda, naturopathy, homeopathy, folk medicine; Energy therapy: healing
touch, energy therapy/reiki, Qi gong; Integrative Medicine Consult, Yoga, and
Exercise were stand-alone categories.

Table 3
3Quality-of-life scores by study visit aMeasure
Baseline
6-week
study visit

12-week
study visit

24-week
study visit

Mean 24-week change
from baseline

P value b

CES-D (0 c -60)
17.9 (10.49)
16.1 (10.93)
15.9 (11.83)
13.8 (11.02)
−4.0 d
<.001

PSS-4 (0 c -16)
6.7 (3.14)
6.2 (3.21)
5.9 (3.52)
6.1 (3.64)
−1.1 d
<.001

SF-12v2 mental (0-100 c )
43.5 (10.44)
45.4 (10.34)
45.6 (10.67)
46.5 (10.97)
3.1 d
<.001

SF-12v2 physical (0-100 c )
37.7 (10.24)
39.4 (10.61)
40.7 (10.72)
41.5 (11.56)
3.7 d
<.001

Quality of sleep (0-10 c )
4.7 (2.91)
5.0 (2.95)
5.1 (2.82)
5.3 (2.80)
0.7 d
<.001

Fatigue scale (0 c -10)
5.8 (2.19)
5.4 (2.32)
5.2 (2.36)
4.9 (2.55)
−0.8 d
<.001

Sense of control (0-10 c )
4.8 (2.47)
5.7 (2.28)
5.8 (2.37)
6.1 (2.45)
1.3 d
<.001

CES-D: Center for Epidemiologic Studies Depression Scale; PSS-4: Perceived Stress Scale-4; SF-12v2: 12-Item Short Form Health Survey.

a

Values per study visit shown are means (SD); mean 24-week change from baseline values from repeated-measures analysis.

b

P value indicates significant change from baseline and 24-week study visit if < .05; obtained from repeated-measures analysis.

c

Indicates better health.

d

Indicates improvement in health.

Table 4
4Work productivity and activity impairment survey measures by study visit a Patients currently employed included in analysis (N = 145); values per study visit shown are means (SD); mean 24-week change from baseline values from repeated-measures analysis. P value indicates significant change from baseline and 24-week study visit if < .05; obtained from repeated-measures analysis.Indicates improvement in health.Measure
Baseline
6-week
study visit

12-week
study visit

24-week
study visit

Mean 24-week change
from baseline

P value b

Absenteeism (%)
8.5 (17.78)
7.8 (16.36)
4.9 (14.00)
5.1 (14.03)
−3.6 c
.035

Presenteeism (%)
36.4 (23.54)
32.3 (25.09)
32.2 (26.12)
29.9 (27.99)
−6.9 c
.002

Work productivity loss (%)
40.8 (25.07)
35.6 (27.67)
33.6 (26.76)
31.0 (28.96)
−10.3 c
<.001

Activity impairment (%)
51.5 (27.64)
45.7 (26.86)
42.3 (27.67)
40.2 (29.80)
−11.1 c
<.001

a

b

c

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AcknowledgementsNone of this would have been possible without the vision and generous support of the Bravewell Collaborative, which funded the creation of BraveNet and this study. The Bravewell Collaborative played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are indebted to our participants for their invaluable contributions to this project. We are also grateful to our site collaborators who contributed enormously to the success of the study: AllianceCompeting interestsCP is a consultant to the Bravewell Collaborative, which funded the creation of BraveNet and this study. The other authors declare that they have no competing interests.Authors' contributionsAll authors participated in the conception and design of the study. DIA, RD, RR, RQW carried out the analyses and drafted the manuscript. All authors read and approved the final manuscript.
. Abbreviations AIOS: Arizona Integrative Outcomes Scale. BPI: Brief Pain InventoryAbbreviations AIOS: Arizona Integrative Outcomes Scale; BPI: Brief Pain Inventory;

Scale; hs-CRP: high-sensitivity C-reactive protein; PSS-4: Perceived Stress Scale-4; SF-12v2: 12-Item Short Form Health Survey; SIMTAP: Study on Integrative Medicine Treatment Approaches for Pain; WPAI: Work Productivity and Activity Impairment. References 1. Institute of Medicine: Relieving Pain in America: A Blueprint for Transforming Prevention. National Academies PressWashington, DCBraveNet: Bravewell Integrative Medicine Research Network; CES-D: Center for Epidemiologic Studies DepressionBraveNet: Bravewell Integrative Medicine Research Network; CES-D: Center for Epidemiologic Studies Depression Scale; hs-CRP: high-sensitivity C-reactive protein; PSS-4: Perceived Stress Scale-4; SF-12v2: 12-Item Short Form Health Survey; SIMTAP: Study on Integrative Medicine Treatment Approaches for Pain; WPAI: Work Productivity and Activity Impairment. References 1. Institute of Medicine: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.

Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States. R L Nahin, P M Barnes, B J Stussman, B Bloom, Natl Health Stat Report. 18Nahin RL, Barnes PM, Stussman BJ, Bloom B: Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States. Natl Health Stat Report 2007, 2009(18):1-14.

Complementary and Alternative Medicine: What People Aged 50 and Older Discuss With Their Health Care Providers. National Aarp, Alternative Center For Complementary, Medicine, Consumer Survey ReportAARP and National Center for Complementary and Alternative Medicine: Complementary and Alternative Medicine: What People Aged 50 and Older Discuss With Their Health Care Providers. Consumer Survey Report; 2010. http://nccam. nih.gov/news/camstats/2010/introduction.htm. Accessed June 29, 2012.

. R Chou, L H Huffman, American Pain SocietyChou R, Huffman LH, American Pain Society;

American College of Physicians: Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/ American College of Physicians clinical practice guideline. Ann Intern Med. 1477American College of Physicians: Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/ American College of Physicians clinical practice guideline. Ann Intern Med 2007, 147(7):492-504.

Education Working Group, Consortium of Academic Health Centers for Integrative Medicine: Core competencies in integrative medicine for medical school curricula: a proposal. B Kligler, V Maizes, S Schachter, C M Park, T Gaudet, R Benn, R Lee, R N Remen, Acad Med. 796Kligler B, Maizes V, Schachter S, Park CM, Gaudet T, Benn R, Lee R, Remen RN, Education Working Group, Consortium of Academic Health Centers for Integrative Medicine: Core competencies in integrative medicine for medical school curricula: a proposal. Acad Med 2004, 79(6):521-531.

. R Q Wolever, D I Abrams, B Kligler, J Frye, J S Edman, S Amoils, J Dusek, E Pradham, R Roberts, M Spar, T Gaudet, M Guarneri, P Homel, S Amoils, R A Lee, D A Monti, B Berman, R Dolor, Patients seek integrative medicine for preventive approach to care. Explore. in pressWolever RQ, Abrams DI, Kligler B, Frye J, Edman JS, Amoils S, Dusek J, Pradham E, Roberts R, Spar M, Gaudet T, Guarneri M, Homel P, Amoils S, Lee RA, Monti DA, Berman B, Dolor R: Patients seek integrative medicine for preventive approach to care. Explore. in press.

Integrative medicine in America: How integrative medicine is being practiced in clinical centers across the United States. B Horrigan, S Lewis, D Abrams, C Pechura, Glob Adv Health Med. 13Horrigan B, Lewis S, Abrams D, Pechura C: Integrative medicine in America: How integrative medicine is being practiced in clinical centers across the United States. Glob Adv Health Med. 2012; 1(3):18-94.

Pain assessment: global use of the Brief Pain Inventory. C S Cleeland, K M Ryan, Ann Acad Med. 232Cleeland CS, Ryan KM: Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994, 23(2):129-138.

A 12-item short form health survey: construction of scales and preliminary tests of reliability and validity. J Ware, M Kosinski, S D Keller, Med Care. 343Ware J, Kosinski M, Keller SD: A 12-item short form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996, 34(3):220-233.

The CES-D scale: a self-report depression scale for research in the general population. L S Radloff, Appl Psychol Meas. 19773Radloff LS: The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977, 1(3):385-401.

A global measure of perceived stress. S Cohen, T Kamarck, R Mermelstein, J Health Soc Behav. 244Cohen S, Kamarck T, Mermelstein R: A global measure of perceived stress. J Health Soc Behav 1983, 24(4):385-396.

Development and validation of a new global well-being outcomes rating scale for integrative medicine research. I R Bell, V Cunningham, O Caspi, P Meek, L Ferro, BMC Complement Altern Med. 4Bell IR, Cunningham V, Caspi O, Meek P, Ferro L: Development and validation of a new global well-being outcomes rating scale for integrative medicine research. BMC Complement Altern Med 2004, 4:1-10.

The validity and reproducibility of a work productivity and activity impairment instrument. M C Reilly, A S Zbrozek, E M Dukes, Pharmacoeconomics. 45Reilly MC, Zbrozek AS, Dukes EM: The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 1993, 4(5):353-365.

Endocrine Society: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. M F Holick, N C Binkley, H A Bischoff-Ferrari, C M Gordon, D A Hanley, R P Heaney, M H Murad, C M Weaver, J Clin Endocrinol Metab. 967Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011, 96(7):1911-1930.

Missing data handling in chronic pain trials. Y Kim, J Biopharm Stat. 212Kim Y: Missing data handling in chronic pain trials. J Biopharm Stat 2011, 21(2):311-325.

Yoga for chronic low back pain: a randomized trial. H E Tilbrook, H Cox, C E Hewitt, A R Kang'ombe, L H Chuang, S Jayakody, J D Aplin, A Semlyen, A Trewhela, I Watt, D J Torgereson, Ann Intern Med. 1559Tilbrook HE, Cox H, Hewitt CE, Kang'ombe AR, Chuang LH, Jayakody S, Aplin JD, Semlyen A, Trewhela A, Watt I, Torgereson DJ: Yoga for chronic low back pain: a randomized trial. Ann Intern Med 2011, 155(9):569-578.

Patient-reported outcomes in studies of complementary and alternative medicine: problems, solutions, and future directions. D T Eton, B A Bauer, A Sood, K J Yost, J A Sloan, Explore. 75Eton DT, Bauer BA, Sood A, Yost KJ, Sloan JA: Patient-reported outcomes in studies of complementary and alternative medicine: problems, solutions, and future directions. Explore 2011, 7(5):314-319.

Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. R H Dworkin, D C Turk, J T Farrar, J A Haythornthwaite, M P Jensen, N P Katz, R D Kerns, G Stucki, R R Allen, N Bellamy, D B Carr, J Chandler, P Cowan, R Dionne, B S Galer, S Hertz, A R Jadad, L D Kramer, D C Manning, S Martin, C G Mccormick, M P Mcdermott, P Mcgrath, S Quessy, B A Rappaport, W Robbins, J P Robinson, M Rothman, M A Royal, L Simon, Pain. 1131-2Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, et al: Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005, 113(1-2):9-19.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. R H Dworkin, D C Turk, K W Wyrwich, D Beaton, C S Cleeland, J T Farrar, J A Haythornthwaite, M P Jensen, R D Kerns, D N Ader, N Brandenburg, L B Burke, D Cella, J Chandler, P Cowan, R Dimitrova, R Dionne, S Hertz, A R Jadad, N P Katz, H Kehlet, L D Kramer, D C Manning, C Mccormick, M P Mcdermott, H J Mcquay, S Patel, L Porter, S Quessy, B A Rappaport, J Pain. 92Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, et al: Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008, 9(2):105-121.

Inflammation in atherosclerosis. P Libby, Nature. 4206917Libby P: Inflammation in atherosclerosis. Nature 2002, 420(6917):868-874.

Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey. M Amer, R Qayyum, Am J Cardiol. 20122Amer M, Qayyum R: Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006). Am J Cardiol 2012, 109(2):226-230.

Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. G A Plotnikoff, J M Quigley, Mayo Clin Proc. 7812Plotnikoff GA, Quigley JM: Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003, 78(12):1463-1470.

Assessing the vitamin D status of the US population. E A Yetley, Am J Clin Nutr. 882Yetley EA: Assessing the vitamin D status of the US population. Am J Clin Nutr 2008, 88(2):558S-564S.

Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. A Bensoussan, N J Talley, M Hing, R Menzies, A Guo, M Ngu, JAMA. 28018Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M: Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA 1998, 280(18):1585-1589.

. National Institutes of Health: PROMIS: Patient-Reported Outcomes Measurement Information System. National Institutes of Health: PROMIS: Patient-Reported Outcomes Measurement Information System. http://www.nihpromis.org. Accessed June 29, 2012.

Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative. S F Garcia, D Cella, S B Clausner, K E Flynn, T Lad, J S Lai, B B Reeve, A W Smith, A A Stone, K Weinfurt, J Clin Oncol. 2532Garcia SF, Cella D, Clausner SB, Flynn KE, Lad T, Lai JS, Reeve BB, Smith AW, Stone AA, Weinfurt K: Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative. J Clin Oncol 2007, 25(32):5106-5112.

The Patient-Centered Outcomes Research Institute (PCORI) national priorities for research and initial research agenda. J V Selby, A C Beal, L Frank, JAMA. 201215Selby JV, Beal AC, Frank L: The Patient-Centered Outcomes Research Institute (PCORI) national priorities for research and initial research agenda. JAMA 2012, 307(15):1583-1584.

Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI): Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. 10.1186/1472-6882-13-146JAMA. 201215Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI): Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. JAMA 2012, 307(15):1636-1640. doi:10.1186/1472-6882-13-146

Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Abrams, BMC Complementary and Alternative Medicine. 13146The BraveNet prospective observational study on integrative medicine treatment approaches for pain. Submit your manuscript at www.biomedcentral.com/submitCite this article as: Abrams et al.: The BraveNet prospective observational study on integrative medicine treatment approaches for pain. BMC Complementary and Alternative Medicine 2013 13:146. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit