WO2009136370A1

WO2009136370A1 - Parenteral supplement with traceelemξntsfor treatment of i. a. sirs, burns selenium-defenciencies

Info

Publication number: WO2009136370A1
Application number: PCT/IB2009/051858
Authority: WO
Inventors: Mette Berger
Original assignee: University Of Lausanne
Priority date: 2008-05-07
Filing date: 2009-05-06
Publication date: 2009-11-12
Also published as: EP2288337A1

Abstract

The present invention addresses the problem of acute deficiencies of trace elements observed in critically ill patients and/or patients receiving parenteral nutrition - toxicity issues are intergrated. In order to solve the problem, the invention provides a kit for parenterally administrating trace elements to a patient, the kit comprising a basic unit of trace elements and at least one supplementary unit, the supplementary unit comprising supplementary trace elements so as to address the specific needs in trace elements of a specific patient. According to an embodiment, the invention provides a supplementary unit for patients diagnosed with SIRS, suffering from burns, patients on continuous renal replacement therapy and patients residing in selenium-poor countries.

Description

PARENTERAL SUPPLEMENT WITH TRACEELEMΞNTSFOR TREATMENT OF I.A. -SIRS, BURNS, SELENIUM-DEFENCIENCIES

Field of the Invention

The present invention relates to the general field of parenteral administration of micronutrients, in particular trace elements. The present invention more particularly relates to a kit for parenteral administration of trace elements to a patient, and to a method of providing intravenous trace elements to a patient.

Background of the Invention and problems to be Solved

Parenteral Nutrition replaces "normal nutrition", which is eating or feeding by the enteral route in patients with gut failure and assimilated conditions. This requires delivering by the intravenous route all the substrates that are required by the body to thrive and which compose normal nutrition. Total parenteral nutrition must deliver the macronutrients (glucose, amino acids, lipids), the micronutrients (electrolytes, vitamins, trace elements), and water. While industrial parenteral nutrition solutions have undergone major evolution regarding the various macronutrients and particularly the amino acid and lipid components, rendering these solutions an adequate alternative to enteral nutrition, there has been no significant evolution on the micronutrients side, or the evolution is limited to the vitamins. In addition, while electrolytes can generally be added to the macronutrient solutions, the vitamins and trace elements have to be provided separately for stability reasons. Indeed presence of micronutrients in parenteral nutrition solutions generally causes instability.

RDAs (recommended daily allowances) for the general population have been replaced by Dietary reference intakes and thereby adapted, generally increased, but such an adaptation has not really been done with intravenous micronutrient recommendations. Only vitamin recommendations and preparations have been modified over the last years, while this has not been the case with trace elements - it is time for a revision. Requirements for parenteral nutrition (PN) have been calculated by analogy with normal feeding on the basis of RDA. Various countries have published guidelines, but these have not been revised since the 70ies or early 80ies. Research has shown that even in stable patients on home parenteral, the doses, which are still in use in the US are not optimal and cause inadequate low tissue levels of some trace elements, while others are too high (e.g. Mn). The European industrial products are probably a little closer to requirements for most trace elements, but there have been issues with too much manganese, which causes encephalopathy (neurological toxicity). Indeed, the potential for trace elements to accumulate and cause toxicity is an important issue. Some trace elements also are significant contaminants of industrially produced solutions, and particularly parenteral nutrition such as chromium, copper, manganese, and zinc.

Further new data in the growingly obese world population give a strengthened role to chromium in the control of glycemia, particularly in diabetes: doses should be reasonably upgraded, but in home parenteral nutrition patients the body chromium concentrations were increased compared to normal.

Altogether, 1 1 essential trace elements, chromium, cobalt, copper, fluor, iron, iodine, manganese, molybdenum, selenium, vanadium and zinc need to be considered.

Accordingly, it is an objective of the present invention to improve the supply of trace elements to patients receiving parenteral nutrition, and/or to those critically ill patients with specific additional requirements, recognizing that there are different requirements in different conditions.

In this context, it is an objective to meet the varying requirements of different patients. It is known that, depending on diagnosis and treatment as well as on residence of a patient, the patient has varying requirements with respect to some trace elements.

It is, in particular, an objective of the present invention to provide sufficient trace elements, while preventing excesses, to patients depending on parenteral nutrition, and further to acutely ill patients suffering from systemic inflammatory response syndrome (SIRS), patients suffering from burns, patients undergoing continuous renal replacement therapy, for example veno-venuous hemofiltration (CVVH), and/or, patients living in selenium deficient areas. Individuals of these groups have different requirements with respect to at least one trace elements, compared to other patients obtaining parenteral nutrition that do not belong to on of these groups. It is also an objective of the present invention to provide trace elements parenterally addressing needs of a specific patient, in a practical way, which can be easily used also by home-based patients.

Summary of the Invention

The present inventor found that requirements of trace elements in patients could be substantially improved by providing a kit of bags or containers, the kit comprising a basic bag and at least one or more supplemental bag(s), which can be combined with said basic bag, wherein an individual receives the trace elements by parenteral administration of the basic bag and, in dependence on the condition, treatment and/or residence of the individual, only the basic bag or at least one supplemental bag is further parenterally administered.

Accordingly, the present inventors learned that individuals suffering from systemic inflammatory response syndrome (SIRS), individuals suffering from burns, individuals undergoing continuous renal replacement therapy, and individuals living in selenium deficient areas have requirements of trace elements that substantially differ from the requirements of other patients receiving parenteral nutrition. While administration of basic trace elements is sufficient for a majority of patients not falling into one of the above-indicated categories, the patients falling in one or more of these categories need to be administered supplemental trace elements in order to meet the patient's needs.

Accordingly, the present invention provides, in a first aspect, a kit for parenteral administration of trace elements to a patient, the kit comprising a basic parenteral unit and at least a supplementary unit, wherein the basic parenteral unit comprises a basic composition of trace elements preferably adapted and/or intended to cover the basal requirements in stable patients, and wherein the said supplementary unit comprises supplementary trace elements so as to meet needs in trace elements of specific conditions and/or of a specific patient.

Preferably, the kit is intended to cover daily requirements of trace elements of a patient that is in a specific acute condition. The kit may be administered to patients suffering from acute conditions whether on parenteral or enteral nutrition support and to patients depending on chronic parenteral nutrition (i.e. home PN). In a second aspect, the present invention provides, a method of providing trace elements to patient, the method comprising the step of administrating a basic parenteral unit comprising basic trace elements, and, in dependence of diagnosis, treatment and/or geographical residence of the patient at least one further supplementary unit, wherein said supplementary unit comprises additional trace elements to meet, together with the basic unit, the specific needs in trace elements of the patient.

Brief Description of the Drawing

Figure 1 is a graphic illustration of the concept according to an embodiment of the present invention. In Figure 1, PN means "parenteral nutrition", SIRS means systemic inflammatory response syndrome, CVVH means continuous veno-venous hemo filtration. Figure 1 thus illustrates how a basic unit is combined with one or more supplementary units in order to provide sufficient trace elements to patients in different conditions.

Detailed Description of the Preferred Embodiments

The present invention relates to a kit for parenterally adminstrating trace elements to a patient. A "kit", for the purpose of the present invention refers to a plurality of different elements, which may be combined and/or connected. The term "kit" reflects the possibility of selecting one, two or more of these elements in order to parenterally administrate trace element to an individual, in particular a patient. The kind and quantity of units to be administered intravenously is preferably selected so as to meet or at least as well as possible the requirements of the patient.

The kit of the present invention comprises a basic parenteral unit and at least one supplementary unit. A "unit" for the purpose of the present invention relates to an entity, which generally may be provided in the form of a bag, a pouch or any other form of container suitable to harbour a liquid and, dissolved therein, the trace elements to be administered parenterally. Preferably, the "unit" is such that the contents are kept sterile and are completely protected from any contamination from the outside. Pouches for parenteral administration of nutrients, medicaments or liquid in general are commercially available. The term "trace elements" for the purpose of the present invention comprises one or more of the elements selected from the group of chromium, cobalt, copper, fluor, iron, iodine, manganese, molybdenum, selenium, vanadium and zinc. According to a preferred embodiment, the expression "trace elements" comprises all these elements.

For the purpose of the present specification, the term "comprises" or "comprising" is intended to mean "includes amongst other", it is not intended to mean "consists only of.

The kit of the present invention comprises a first unit, also referred to herein as "basic unit", "basic parenteral unit" and the like. The first unit comprises a basic composition of trace elements intended to provide sufficient trace element to a patient not falling into one or more of the specific categories of patients, which have different requirements at least in one trace element, and in general higher requirements in one or more trace elements. Preferably, the basic unit comprises trace elements in sufficient amounts for patients who do not suffer from SIRS, who did not suffer from burns, who do not undergo a continued renal replacement therapy, and who are residents of selenium-rich areas. The "PN basis" constitutes the founding element of the kit, whether the patient depends on parenteral nutrition or not. The

"basic" unit is thus intended to meet the basic requirements in trace elements of a patient who does not have particular and/or specific requirements due to the circumstantial conditions and/or acute conditions he/she find himself/herself, such as defined, for example, by the specific categories described herein. It is particularly suited for patients on home PN.

Preferably, the basic unit comprises the following trace elements at the indicated amounts: 2- 3 μg of chromium; 0-5 μg, preferably 1-4 μg of cobalt; 0.3-0.4 mg of copper; 1.4-1.5 mg fluor; 0.5-1 mg iron; ≤ 50 μg iodine; 20-30 μg molybdenum; 40-80 μg selenium; 8-10 mg, preferably 9-10 mg zinc; wherein the indicated amounts correspond to a daily administration dose.

Preferably, the basic unit is free of vanadium or comprises ≤ 1 μg vanadium.

The daily administration dose, being the dose or amount of trace elements to be administrated to a patient on a daily basis, is preferably contained in one bag. For example, the trace elements of the basic unit are contained in a container containing 25-60 ml of an aqueous solution, preferably a 30-50 ml, and most preferably a 35-45 ml of an aqueous solution of the trace elements to be administrated on a daily basis as indicated above. The patient is administered parenterally one basic unit per day, preferably in the form of a single container.

The kit according to the present invention comprises one or more supplementary unit(s) comprising supplementary trace elements. The supplementary unit is administrated in addition to the basic unit in order to meet the specific increased needs in some trace elements of patients suffering from a specific condition, patients undergoing specific therapies and/or patients being residents of a specific region.

Patients suffering from or being in a specific condition, for example patients suffering from burns, and/or patients diagnosed with severe systemic inflammatory response syndrome (SIRS) have specific requirement with respect to trace elements. In general, in these patients requirements in some selected trace elements are higher, as detailed further below.

Similarly, patients residing in specific areas may have higher requirements in at least one trace element, because in this area, normal nutrition generally is deficient in one or more trace elements. This may be due low soil contents of a trace element in some areas, as detailed further below. Accordingly, the present invention provides a supplementary unit for compensating deficiency in trace elements in patients due to low contents of said trace elements in the area of their residence.

Furthermore, patients undergoing a specific therapy, for example patients subjected to continuous renal replacement therapy, such as continuous veno-venous hemo filtration (CVVH), have specific requirement with respect to trace elements, caused by the continuous losses of trace elements in the effluent. In general, in these patients requirements in most trace elements are higher, as detailed further below.

Accordingly, the present invention provides at least a first, and optionally a second, a third, a fourth or more supplementary units comprising supplementary trace elements so as to meet needs in trace elements of a specific patient and/or patient population. Preferably, each supplementary unit is assigned to a specific category of patients, the category grouping patients characterised by similarly changed needs in trace elements with respect to patients of another category or with respect to basic requirements. According to an embodiment, the supplementary unit, for example the first, the second, the third and/or the fourth supplementary unit, comprises trace elements to address the specific needs of a patient selected from the group consisting of: (1) a patient suffering from an intense systemic inflammatory response syndrome (SIRS),

(2) a patient suffering from burns;

(3) a patient undergoing continuous renal replacement therapy; and,

(4) a patient living in selenium deficient areas.

With respect to (1) above, the patient is preferably a critically ill patient suffering a condition with an intense systemic inflammatory response syndrome.

For the purpose of the present specification it is clarified that the expression "address the needs in trace elements of a specific patient" or "meet the requirements in trace elements of a patient" or of a patient population and similar expressions are not understood as providing the exact amount of trace elements required by a given individual. It needs to be understood that it is nearly impossible to meet the exact needs in trace elements of a given individual in a hospital environment. The exact need of an individual depend on far too many factors, which can only hardly be captured. For example, individual needs in trace elements may depend on age, sex, size and other factors, the totality of which is hard to evaluate. In contrast, the present invention has the objective to more approximately meet the requirements of patients falling in a category or group of patients who, according to the knowledge of the inventor, have substantially higher need in some specific trace elements. The present invention intends to prevent important deficiencies in trace elements in patients, for example hospitalised individuals and/or patients receiving parenteral nutrition or supplements at home. The present also has the goal of avoiding toxic accumulation of trace elements in a patient.

According to the present specification, patients falling into one of the categories defined herein form a specific patient population. It is indicated that the present invention also encompasses categories of patients, or patient populations, that are not disclosed herein, but that will be identified later as a group of patients having requirements in trace elements specifically differing from the requirements of any category defined herein. The present invention also encompasses the possibilities that the definition of a specific category of patients and/or patient population as defined therein is refined. The present invention, of course, also encompasses the possibility that the amounts of trace elements of the basic unit and any supplementary unit be redefined. If, for example, it turns out that patients not falling in one of the particular categories defined herein, or an other specific category are not adequately provided with trace elements by the basic unit, the invention encompasses an adaptation of the basic unit, and, if adequate of any of the supplementary units.

According to a preferred embodiment, the kit of the present invention comprises a supplementary unit for providing supplementary trace elements to a patient and/or a patient population suffering from systemic inflammatory response syndrome (SIRS).

Without wishing to be bound by theory, the inventor, on the basis of her experience and evidences from medical literature, notes that critically ill SIRS patients are exposed to an increased oxidative stress, due to their condition, to the associated inflammatory response, and also to the side effects of some of the intensive care unit (ICU) treatments such as mechanical ventilation using high inspired fractions of oxygen, transfusion of erythrocytes, and continuous renal replacement therapy. Injured tissues produce free radicals, and inflammation amplifies this reaction. The oxygen derived radicals (ROS), which are produced under normal aerobic metabolism mainly by leukocytes and by the respiratory mitochondrial chain) are essential for cell signaling, and for bacterial defense. The nitric oxide derived radicals (NOS) are normal by-products of endothelial metabolism. ROS activate the nuclear transcription factor kappa B (NFKB), which is one of the steps of the amplification of SIRS. This activation is attenuated by several "antioxidant" micronutriments, such as selenium (Se) zinc (Zn) and vitamins C and E.

Again, without wishing to be bound by theory, it is considered that endogenous antioxidant defenses are largely enzymatic and dependent for activity on trace elements, in particular Cu, Se, Mn, and Zn. Cu, Zn and Mn are required by the superoxide dismutases (SOD), Se by the glutathione peroxidases (GPX), and Cu and/or Fe by catalase. The antioxidant enzymes exert their activities in the cytosol, in mitochondria, or in plasma. The SODs initiate the antioxidant process, transforming the superoxide anion into hydrogen peroxide. The later is metabolized by catalase, and further by the different types of GSHPx, which neutralize the various peroxides. Tissue concentrations of these antioxidants is strongly depressed after burn injury in a rat model and in burned patients. Selenium appears to be particularly affected by the alterations caused by SIRS, while being central in the antioxidant defence as part of the GPX. The activity of the plasma GPX is highly dependent on selenium whatever the condition. It is particularly depressed in patients with an intense inflammation such as sepsis, pancreatitis, major burns and acute and chronic renal failures.

As a consequence of the above stated, the requirements for these elements involved in antioxidant defense mechanisms are increased above the basal nutritional requirements. The balance between the amount of ROS and natural scavengers of free radicals determines the outcome of local and distant tissue damage and further organ failure in burn injury, and in some other severe intensive care conditions. If prolonged, this inflammation favors development of organ failure.

Antioxidant and immune defenses are closely linked. It was demonstrated that selenium deficiency favors the development of virus virulence and subsequent infections through the reduction of GPX activity. The present inventor thus find that "oxidation" and "antioxidation" are an essential step in defenses against infection. In addition a series of trace elements, in particular Cu, Se, Fe, and Zn, and vitamins in particular vitamins C et E may be involved in immune defenses, probably through antioxidant mechanisms.

Patients with severe sepsis or septic shock and those with SIRS without infection should be differentiated, and the doses delivered should be different, smaller in the later case. Indeed selenium may have side effects and even be toxic. It may cause alterations of thyroid hormone metabolism, which occurs in the general population with chronic daily intakes above 450 μg/day, while selenosis is described above 750 μg/day.

In consideration of the above, the present invention provides a supplementary unit for the category of patients suffering from SIRS. This supplement mainly aims at reinforcing endogenous antioxidant defences.

SIRS is found in specific severe critical care conditions, for example those selected from severe sepsis or septic shock of any origin, pancreatitis, acute respiratory distress syndrome (ARDS), major trauma and organ transplantation, in particular heart, kidney, liver and/or lung transplantation. According to a preferred embodiment, the supplementary unit to be administered, in addition to the basic unit, to patients sustaining SIRS comprises 200-500 μg selenium, for example 200-300 μg selenium, 5-10 mg zinc, and 10-20 μg chromium, wherein these amounts correspond to a daily administration dose for patients diagnosed with SIRS. These trace elements may be dissolved, for example in about 20-40 ml water and filled in a corresponding bag.

According to another embodiment, the kit of the present invention comprises a supplementary unit for providing supplementary trace elements to patients suffering from burns.

Deficiencies in various trace elements have been repeatedly described since 1960 in patients suffering from major burns. They are proportional to the burn surface (i.e. to burned % of body surface area, abbreviated BSA hereafter) and are associated with wound healing and infectious complications. Without wishing to be bound by theory, the trace element deficiencies are largely explained by extensive cutaneous exudative losses and to a lesser extent, by urinary losses, drains, and hemorrhage, which cause negative micronutrient balances during the first week after injury.

Without wishing to be bound by theory, the alterations of trace element status observed in burns are reflected among others, by low plasma trace element concentrations which persist for many weeks after injury, and which are multifactorial. The interpretation of the low plasma levels is complicated by SIRS, which is characterized by decreased plasma trace element levels. It was reported that during the inflammatory response micronutrients are redistributed. Accordingly zinc is moved from the circulating compartment and from reserves (muscle, skin, bone) to tissues with rapid cell proliferation and intense protein synthesis, particularly thymus, bone marrow and liver. The oxidative stress caused by burns stimulates the expression of the transport protein metallothionein (MT) which increases in the liver due to the rapid raise of the expression of its MT-I mRNA: this stimulation is probably caused by the increase in lipid peroxides. As a consequence, the serum concentrations of most trace elements and of their carrier proteins decrease, causing an unbalance in circulating antioxidants, which are supposed to be able to limit the release of NFkB caused by increased ROS. It has been hypothesized that the redistribution of trace elements occurring during the acute phase response may be deleterious if prolonged. Without wishing to be bound by theory, the inventor finds, on the basis of her knowledge and information from selected literature, that copper deficiency is specific of burns and has been described for many years both in children and in adults. When the injury involves 30% BSA or more, patients can lose 20-40% of their body Cu content within the first week of injury with their exudates. A further study in severely burned children confirmed exudative Cu and Zn losses. Plasma Cu concentration remains low for weeks, proportionally to burn size. The deficiency may be severe enough to cause fatal arrhythmias.

Further, without wishing to be bound by theory, it appears that oxidative stress and lipid peroxidation is particularly intense in burns, and caused in part by the direct effect of the burn on skin lipids, and by an increased free radical production, which is initiated directly by the burn, and indirectly by leukocytes. In burns involving more than 20% BSA, the inflammatory response spreads rapidly to the whole body, resulting in a general capillary leak syndrome, with edema formation. Experimental studies have shown that there is a close relationship between a lipid peroxide reaction and secondary pathological changes following burns. As long as wounds are not closed, inflammation is reactivated by microorganism proliferation, endotoxin production and surgery.

According to a preferred embodiment of the present invention, the supplementary unit to be administrated, in addition to the basic unit, to a patient and/or a patient population suffering from burns comprises: 3-4 mg copper; 300-500 μg selenium; and 30-40 mg zinc, wherein these amounts correspond to a daily administration dose for these patients. This daily dose is preferably to be administered for 7-8 day in patients with burns on 20-30% of BSA, for 14-21 days, for example 14-15 days, in burns of 30-50% of BSA, and for 21-30 days, for example 21-25 days, with burns exceeding 50% of BSA. In other words, percentage of the body surface affected by burns preferably determines the length of administration of the supplementary unit for patients suffering from burns. In children, the dose to be delivered is first adapted to the child's size (total BSA): the above figures were determined for adults having a body surface of 1.8 m². Thereafter the burned size is taken into account as in adults (see above). The supplementation may have to be resumed later based on low plasma in case of persistent open burn wounds. The trace elements of the supplementary unit for patients suffering for burns may be dissolved, for example, in about 100-200 ml water and filled in corresponding bags. Patients suffering from burns are preferably provided with enteral nutrition, with the trace elements of the kit of the present invention being administered by the intravenous route.

According to another embodiment, in a patient and/or a patient population undergoing any kind of continuous renal replacement therapy the present invention provides a supplementary unit to be administered in addition to the basic unit comprising: all the elements of the basic unit at the indicated quantities, and, in addition + 100-200 μg of selenium per daily administered dose. In other words, patients undergoing continuous renal replacement therapy receive two basic units and a supplementary unit comprising 100-200 μg, preferably 100- 150 μg of selenium per day. The trace elements of the supplementary unit for patients undergoing a renal replacement therapy may be dissolved, for example, in about the same amount of water as the basic unit, preferably in at least about 35 ml water and filled in an appropriate bag.

According to an embodiment, the supplementary unit for patients undergoing continuous renal replacement therapy comprises, in addition to selenium as indicated above zinc, for example, 7-10 mg zinc.

For example, the continuous renal replacement therapy is continuous veno-venuous hemofϊltration (CVVH).

In critically ill patients on continuous renal replacement therapy, the plasma concentrations of trace elements are particularly low, far below the normal reference ranges. Without wishing to be bound by theory it is believed that trace elements are lost through filters used in replacement therapy.

According to another embodiment, the present invention provides a supplementary unit for providing supplementary trace elements to a patient and/or a patient population living in Se- defϊcient geographic areas, said supplementary unit comprising 150-250 μg, preferably 180- 220μg selenium per daily administered dose. The trace element for this supplementary unit may, for example be dissolved in about 15-25 ml water and filled in an appropriate bag, or into the basic unit pouch or bottle. Selenium deficiency affects the muscles and squelettal system. It results in cardiomyopathy (Keshan disease), which can be lethal, and musculo-squelettal disorders (Kashin Beck disease), and in late stages hair and nail alterations. They typically occur in areas with extremely low soil content. Some areas of the globe are characterized by very low soil contents of selenium. Europe is one of these areas, and low plasma concentrations have repeatedly been shown in the general population of many European countries. One European country, Finland, has taken action and used fertilization to successfully improve the status of cattle and then humans, by altering the complete food chain's selenium content and adapting progressively the fertilization dose to the observe responses. Other areas are New Zealand and Australia, California, and the Chinese Keshan province. In contrast, some other areas of the world are seleniferous such as most of the US, Canada, Venezuela and some areas of China, with their populations having high-supra normal plasma concentrations of selenium. The supplementation of the selenium should therefore integrate these geographic differences.

As described with respect to the basic unit above, the daily administration dose of a supplementary unit is preferably contained in one container, for example a pouch. For example, the trace elements of the supplementary unit destined for SIRS patients are within a 20-40 ml container of an aqueous solution of the trace elements to be administrated on a daily basis as indicated above. Preferably, the patient is administered parenterally one supplementary unit per day, preferably in the form of a single container. The supplement units may also be presented in dry powder form to be diluted with the basic unit. An exception is formed by the patients undergoing continuous renal replacement therapy, which receive, in total, two doses of the basic unit and in addition, a bag containing 100 μg selenium. With these patients, one basic unit is considered as a supplementary unit, together with the additional selenium. Therefore, in this case, the supplementary unit may be administered in the form of two separate bags. It could also be envisaged to provide a supplementary unit in the form of a single bag for patients on continuous renal replacement therapy, which contains all the elements of the basic unit and, in addition, the additional selenium.

A supplementary unit according to the present invention may be administered directly through a suitable intravenous line. Alternatively, it may be conceived to be susceptible of being branched, for example via a tube, to a receiving port of the basic unit. In this case, the contents of the supplementary unit may be guided through the pouch of the basic unit. This is possible, for example, if the mixing of the contents of the basic unit and the supplementary unit occurring in this case does not cause any stability problem or other kind of non- compatibility. Alternatively, the basic and any supplementary unit may be administered successively, by infusing the contents of a container comprising the basic unit or of a supplementary unit through an intravenous catheter into a patients blood stream, and, once the container is empty, de-branching the empty container from the catheter and branching another container comprising a basic unit or a supplementary units, as adequate, through the same catheter. The supplementary units may also be presented as a concentrate or a dry powder to be diluted or dissolved, respectively. For example, a concentrate or dry powder may be diluted with the basic unit. Different ways of administrating the basic unit and any supplementary unit may be conceived by the skilled person, which are encompassed by the present invention. Preferably, the different supplementary units may all be administrated in the same way, so that medical personnel or a patient at home is not required to use different administration procedures depending on which supplementary unit is administrated.

The present specification discloses four (4) different supplementary units to improve the requirements in trace elements of four different patient populations or four categories of patients. However, in a simpler embodiment of the invention, the kit of the present invention may comprise the basic unit and only one single supplementary unit of trace elements. In another embodiment, the kit comprises two, three, four, or generally n supplementary units, with n being an integer from 5 upwards. Of course, for practical reasons, it is a goal of providing as few supplementary as possible, but, for medicinal reasons, as many as necessary so as to avoid deficiencies and toxicity in a specific patient or patient population.

It is expressly stated that the mechanistic explanations and explanatory remarks associated with deficiencies of trace elements or increased need of some trace elements of specific categories of patients and/or patient populations given herein above expresses the inventor's viewpoint and knowledge at the moment of the filing of the present application. They are based on the inventor's knowledge of the literature and knowledge gained in research done in the area of requirements of trace elements. These statements are meant to provide further insight to the skilled person and are not intended as a limitation by theory. In case some of the mechanistic explanations and observations should turn out to be wrong or not as relevant as believed, this should by no means be interpreted as a limitation of the general concept of the present invention. It may also be that although some mechanistic explanations may turn out not to be correct, the amounts of trace elements to be administered still apply. It may also be that some amounts of some trace elements may need to be adjusted once further information is available.

According to an embodiment, the present invention provides that the supplementary unit for patients of Se-defϊcient areas can be combined with one of the complementary parenteral units selected from the unit designed to patents suffering from SIRS and the unit designed for patients undergoing continuous renal replacement therapy. The expression "can be combined with" means that the supplementary unit for patients from Se-defϊcient areas can be administered in addition to (or together with) a supplementary unit selected from the supplementary unit for SIRS patients and the supplementary unit for patients on continuous renal replacement therapy.

Amongst the supplementary units disclosed herein, only the one for patients residing in Se- poor regions are designed to be combined with other supplementary units, namely with the one for SIRS patients and the one for patients undergoing continuous renal replacement therapy, as illustrated in Figure 1. Other supplementary units are not designed to be combined with each other. Such combination not specifically mentioned herein could lead to toxic accumulation of trace elements.

The kit of the present invention is preferably designed for parenteral administration to a critically ill patient and/or a acutely ill patient, whether or not the patient receives total parenteral nutrition.

The kit of the present invention is preferably administered to patients over a central venous line, as trace elements are irritant to small peripheral veins. Accordingly, the basic unit is generally parenterally administered for the same time period as the total parenteral nutrition, if applicable, while the supplementary units (in combination with the basis) are administered for the duration of the acute condition but at least for 5 days, even in patients not requiring parenteral nutrition. If in the course of parenteral nutrition, the condition of a patient changes, the supplementary unit(s) that is (are) administered may need to be adapted. For example, if the condition of a patient suffering from burns improves substantially, administration of the corresponding supplementary unit may be stopped as determined by the medically trained person in charge for the patient. According to a preferred embodiment, the basic unit and, preferably, any supplementary unit, is substantially free of macronutrients, in particular, the units are substantially free from glucose sources, lipids, and more preferably also from proteinogenic sources, such as proteins, peptides, and amino acids. In this way, problems of instability of compositions for total parenteral nutrition because of the presence of trace elements are avoided. "Substantially free of macronutrients", for the purpose of the present invention, refers to ≤ 10% by weight of dry matter, preferably ≤ 5%, more preferably ≤ 3% by weight of dry matter of macronutrients. Preferably, the basic and/or supplementary unit(s) is/ are completely free of macronutrients, that is, do not contain any trace elements.

Each unit may contain stabilisers, buffers and other additives, as adequate. In principle, an additive could be a "macronutrient" in the large sense of the term, if a patient can derive energy from metabolising the additive. However, in this case, for the purpose of the present invention, the additive would not fall under the expression "macronutrient" as defined herein, because the stabilisers and/or buffers are generally provided in small quantities not designed to meet nutritional requirements of a patient and because the additive is added for the purpose of fulfilling a specific function in the unit, generally for stabilising or conserving the unit in its container, or for making the contents of the container compatible for parenteral administration to humans, which function is not directly related to the nutrition of a patient. In general, the basic unit and any supplementary unit according to the invention is preferably not intended to provide macronutrients in amounts sufficient to provide complete nutrition to a patient.

As an exception to the above said, it is indicated that in certain patients, specific macronutrients may be added if it is considered that the respective macronutrient is important for the specific condition. For example, there are nutrients that are not essential for a healthy person, but which become conditionally essential for patients suffering from a specific condition. For example, certain amino acid and/or fatty acids may be conditionally essential with some conditions and may thus be added to any one of the units mentioned herein, in particular to a supplementary unit. A more specific example is the SIRS unit, which may be combined with a conditionally essential amino acid such as glutamine, which is a conditionally essential in critically ill patient. Therefore, according to an embodiment, one or more units, and in particular one, several or all of the supplementary units, may comprise nutrients, including macronutrients, in particular those which are conditionally essential for the patient and/or patient population for which the supplementary unit is provided.

According to a preferred embodiment, the basic unit and/or a supplementary unit according to the present invention essentially consist of the trace elements mentioned herein in the indicated amounts and is free of further nutrients.

The indications given in the above two paragraphs do not apply, of course, to electrolytes that are contained in a unit because of the process preparation. More particularly, the trace elements are generally added in the form of a salt comprising the trace element in ionic form together with another ion of opposed charge. The salt is then added in corresponding amounts to an aqueous solution so as to prepare the basic unit or any supplementary unit according to the present invention. The trace elements can be prepared as salts or as organic compounds (gluconate). In general, each unit comprises an aqueous solution of one or more trace elements, each trace element being added in the preparation of the solution in the form of a salt, wherein a counterion in the salt is selected so as not to affect negatively, in the corresponding amounts, the health of the individual. It may also be useful to provide salts consisting of an anionic and a cationic trace element, so as to avoid the use of trace elements that are not specifically needed.

The compositions, units, kits, aqueous solutions and so forth of the present invention are typically sterile formulations and are prepared according to conventional manufacturing techniques using for example aseptic manufacture or terminal sterilisation by autoclaving. In addition, all components of the compositions, units, kits, aqueous solutions and so forth of the present invention are preferably at least United States Pharmacopeia (USP)-grade purity, which is generally a purity of about 95%. The purity of the components is preferably at least about 95%, more preferably at least about 98%, and more preferably at least about 99%.

According to an embodiment, the recommended duration of administration is intended to be different for the various supplements:

Basic unit: for as long as the patient requires parenteral nutrition; Burns: for the duration specified above in dependence of the affected BSA. It may have to be resumed for about 5 days periods in patients with document low plasma copper, zinc or selenium levels;

CVVH: for the duration of renal replacement therapy; SIRS: for 5 days.

The examples below illustrate the invention without limiting its scope.

Examples

Example 1 : Preparation of a basic unit according to the present invention

A basic unit for parenterally administrating trace elements to a patient is prepared by dissolving trace elements as shown in Table 1 under aseptic conditions in 40 ml water:

Table 1: Composition of an exemplary basic unit

Trace element Amount

Chromium 2.5 μg

Cobalt 1 mg

Copper 0.35 mg

Fluor 1 mg

Iron 1 mg

Iodine 0.05 μg

Manganese 0

Molybenum 25 μg

Selenium 75 μg

Vanadium 0.5 μg

Zinc 10 me.

The aqueous solution is aseptically filled in a sterile 40 ml bag.

Example 2: Supplementary unit for patients diagnosed with SIRS

A supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient suffering from SIRS is prepared by dissolving trace elements as shown in Table 2 under aseptic conditions in 40 ml water:

Table 2: Composition of an exemplary supplementary unit for SIRS patients Trace element Amount

Chromium 20 μg

Selenium 300 μg

Zinc 15 me.

The aqueous solution is aseptically filled in a sterile 40 ml bag.

Example 3 : Supplementary unit for patients suffering from burns

A supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient suffering from burns is prepared by dissolving, under aseptic conditions, trace elements as shown in Table 3 in 200 ml water:

Table 3: Composition of an exemplary supplementary unit for patients suffering from burns

Trace element Amount

Copper 3.5 mg

Selenium 350 μg

The aqueous solution is aseptically filled in a sterile 200 ml bag.

Example 4: Supplementary unit for patients on continuous renal replacement therapy

A supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient on CVVH is prepared by dissolving, in addition to all the trace elements of Table 1 in the amounts indicated in Table 1 , 100 μg selenium in 40 ml water.

This supplementary unit thus differs from the basic unit only in that more selenium is present. The patient is administered the basic unit and this supplementary unit, which means twice that basic unit and, additionally, 100 μg selenium are daily administered to a patient on CVVH. The aqueous solution is aseptically filled in a sterile 40 ml bag.

Example 5 : Supplementary unit for patients from selenium poor areas

A supplementary unit for parenterally administrating supplementary trace elements, in addition to the basic unit of example 1 to a patient generally residing in a selenium poor area is prepared by dissolving, under aseptic conditions, 100 μg selenium in 20 ml water. The aqueous solution is aseptically filled in a sterile 20 ml bag.

Example 6: Contemplative Example

A female 38 years old patient is admitted to the intensive care unit of a hospital for deep surgical burns involving 40% of her body surface to the right arm, back and the abdomen. Her weight is 70 kg.

The patient is put on enteral nutrition and the kit of the present invention is used to parenterally provide trace element - delivering one basic kit + 1 burns supplement for 21 days through a central parenteral line. The patient thus is administered the basic unit of example 1 and the supplementary unit for patients suffering from burns of example 3.

Thanks to the administration of trace elements according to the invention, the patient receives sufficient trace elements over the whole period of treatment. In particular, she will not experience any deficiencies in copper, selenium and zinc.

After 21 days of treatment the parenteral administration of trace elements is stopped while the enteral nutrition is continued until week 5 and. The patient's plasma concentrations of copper, selenium and zinc are close to normal.

Had this patient been administered daily doses of trace elements according to the prior art, she would have suffered deficiency in copper, selenium and zinc trace elements. A prolonged healing process and hospital stay would have been the consequence. Literature:

Basic trace elements:

Standing, Committee, on, et al: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2001). http://booksnapedu/catalog/10026html 2001;

Food, and, Nutrition, et al: Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D. C: National Academy Press; 2001 FDA: Parenteral multivitamin products; Drugs for human use; Drug efficacy study implementation; Amendment. Federal Register 2000; Volume 65:Number 77

Shils ME, Burke AW, Greene HL, et al: Guidelines for essential trace element preparations for parenteral use. JAMA 1979; 241 :2051-2054

Howard L, Ashley C, Lyon D, et al: Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration formulation. JPEN J Parenter Enteral Nutr 2007; 31 :388-396

Taylor S, Manara AR: Manganese toxicity in a patient with cholestasis receiving total parenteral nutrition. Anaesthesia 1994; 49:1013

Wardle C, Forbes A, Roberts NB, et al: Hypermanganesemia in long-term intravenous nutrition and chronic liver disease. J Parent Ent Nutr 1999; 23:350-355

SIRS:

Ghosh D, Bhattacharya B, Mukherjee B, et al: Role of chromium supplementation in Indians with type 2 diabetes mellitus. J Nutri Biochem 2002; 13:690-697 Berger MM: Can oxidative damage be treated nutritionally? Clin Nutr 2005; 24:172-

183

Agay D, RD Anderson, Sandre C, et al: Alterations of antioxidant trace elements (Zn, Se, Cu) and related metaloenzymes in plasma and tissues following burn injury in rats. Burns 2005; 31 :366-371 Berger MM, Shenkin A: Update on clinical micronutrient supplementation studies in the critically ill. Curr Opin Clin Nutr Metab Care 2006; 109:711-716

Cetinkale O, Belce A, Konukoglu D, et al: Evaluation of lipid peroxidation and total antioxidant status in plasma of rats following thermal injury. Burns 1997; 23:114-116 Beck MA: Selenium and host defence towards viruses. Proceedings of the Nutrition Society 1999; 58:707-711

Hey land DK, Dhaliwal R, Suchner U, et al: Antioxidant nutrients: A systematic review of trace elements and vitamins in the critically ill. Intensive Care Med 2005; 31 :321- 337

Angstwurm MW, Engelmann L, Zimmermann T, et al: Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 2007; 35:118-126 Forceville X, Laviolle B, Annane D, et al: Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study. Crit Care 2007; 11 :R73

Bratter P, Negretti de Bratter VE: Influence of high dietary selenium intake on the thyroid hormone level in human serum. J Trace Elem Med Biol 1996; 10:163-166 Anderson RA, Sandre C, Bryden NA, et al: Burn- induced alterations of chromium and the glucose/insulin system in rats. Burns 2006; 32:46-51

Yun-Yu C: Selenium and Keshan disease in Sichuan province, China. New York: Van Nostrand Reinhold Company; 1984

Selenium:

Utiger RD: Kashin-Beck disease-expanding the spectrum of iodine-deficiency disorders. New Engl J Med 1998; 339:1156-1158

Hercberg S, Preziosi P, Galan P, et al: Apports nutritionnels d'un echantillon representatif de Ia population du Val-de-Marne: III. les apports en mineraux et vitamines. Rev Epidem Sante Publ 1991; 39:245-261

Maksimovic ZJ, Djujic I, Jovic V, et al: Selenium deficiency in Yougoslavia. Biol Trace Elem Res 1992; 33:187-196

Oster O, Schmiedel G, Prellwitz W: The organ distribution of selenium in German adults. Biol Trace El Res 1988; 15:23-65 Rayman MP: The importance of selenium to human health. Lancet 2000; 356:233-241

Rayman MP: Dietary selenium: time to act. Br Med J 1997; 314:387-388 Vara P, Alfthan G, Ekholm P, et al: Selenium intake and serum selenium in Finland: effects of soil fertilization with selenium. Am J Clin Nutr 1988; 48:324-329 Lyons GH, Judson GJ, Ortiz-Monasterio I, et al: Selenium in Australia: selenium status and biofortifϊcation of wheat for better health. J Trace Elem Med Biol 2005; 19:75-82

Agay D, Sandre C, Ducros V, et al: Optimization of selenium status by a single intraperitoneal injection of Se in Se deficient rat: possible application to burned patient treatment. Free Rad Biol Med 2005; 39:762-768

Alfthan G, Neve J: Reference values for serum selenium in various areas - Evaluated according to the TRACY protocol. J Trace Elements Med Biol 1996; 10:77-87

Yang G , Zhou R: Further observations on the human maximum safe dietary selenium intake in a seleniferous area of China. J Trace Elem Electr Hlth Dis 1994; 8:159-165

Burns:

Berger MM, A Shenkin: Trace element requirements in critically ill burned patients. J Trace Elem Med Biol 2007; 21 (suppl l):44-48

Berger MM, Cavadini C, Bart A, et al: Selenium losses in 10 burned patients. Clin Nutr 1992; 11 :75-82

Berger MM, Cavadini C, Bart A, et al: Cutaneous zinc and copper losses in burns. Burns 1992; 18:373-380

Berger MM, Rothen C, Cavadini C, et al: Exudative mineral losses after serious burns: A clue to the alterations of magnesium and phosphate metabolism. Am J Clin Nutr 1997; 65:1473-1481

Hunt DR, Lane HW, Beesinger D, et al: Selenium depletion in burn patients. Journal of Parenteral & Enteral Nutrition 1984; 8:695-699

Voruganti VS, Klein GL, Lu HX, et al: Impaired zinc and copper status in children with burn injuries: need to reassess nutritional requirements. Burns 2005; 31(6):711-716 Shenkin A: Trace elements and inflammatory response: implications for nutritional support. Nutrition 1995; 11 :100-105

Ding HQ, Zhou BJ, Liu L, et al: Oxidative stress and metallothionein expression in the liver of rats with severe thermal injury. Burns 2002; 28:215-221

LaLonde C, Nayak U, Hennigan J, et al: Excessive liver oxidant stress causes mortality in response to burn injury combined with endotoxin and is prevented with antioxidants. JBCR 1997; 18:187-192

Saez J C, Ward PH, Gϋnther B, et al: Superoxide radical involvement in the pathogenesis of burn shock. Circulatory Shock 1984; 12:229-239 Hart DW, WoIf SE, Mlcak R, et al: Persistence of muscle catabolism after severe burn. Surgery 2000; 128:312-319

Allgόwer M, Schoenenberger GA, Sparkes BG: Burning the largest immune organ. Burns 1995; 21 :S7-S47 Berger MM, Spertini F, Shenkin A, et al: Trace element supplementation modulates pulmonary infection rates after major burns: a double blind, placebo controlled trial. Am J Clin Nutr 1998; 68:365-371

Berger MM, Eggimann P, Heyland DK, et al: Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggregation of two randomised trials. Crit Care 2006; 10:R153:e-pub 2 Nov

Continuous renal replacement therapy:

Berger MM, Shenkin A, Revelly JP, et al: Copper, selenium, zinc and thiamine balances during continuous venovenous hemodiafiltration in critically ill patients. Am J Clin Nutr 2004; 80:410-416

Richard MJ, Ducros V, Foret M, et al: Reversal of selenium and zinc deficiencies in chronic hemodialysis patients by intravenous sodium selenite and zinc gluconate supplementation - Time-course of glutathione peroxidase repletion and lipid peroxidation decrease. Biol Tr Elem Res 1993; 39:149-159 Story DA, Ronco C, Bellomo R: Trace element and vitamin concentrations and losses in critically ill patients treated with continuous venovenous hemo filtration. Crit Care Med

1999; 27:220-223

Metnitz GH, Fischer M, Bartens C, et al: Impact of acute renal failure on antioxidant status in multiple organ failure. Acta Anaesthesiol Scand 2000; 44:236-240 Yoshimura S, Suemizu H, Nomoto Y, et al: Plasma glutathione peroxidase deficiency caused by renal dysfunction. Nephron 1996; 73:207-211

Angstwurm MWA, Schottdorf J, Schopohl J, et al: Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care

Med 1999; 27:1807-1813 Nakamura AT, Btaiche IF, Pasko DA, et al: In vitro clearance of trace elements via continuous renal replacement therapy. J Ren Nutr 2004; 4:214-219

Claims

1. A kit for parenteral adminstration of trace elements to a patient, the kit comprising a basic parenteral unit and at least a supplementary unit, wherein the basic parenteral unit comprises a basic composition of trace elements and wherein the said supplementary unit comprises supplementary trace elements so as to meet needs in trace elements of a specific patient.

2. The kit of claim 1, wherein the specific patient (a) is diagnosed with and/or suffering from a specific condition, (b) is subjected to a specific medical treatment, (c) is a resident of a specific geographical region.

3. The kit of any one of claims 1 or 2, wherein said supplementary unit is a first supplementary unit and wherein the kit further comprises one or more further supplementary unit, said one or more further supplementary unit being a second, a third, a fourth and an nth supplementary unit, with n being an integer > 5, said one or more further supplementary unit comprising supplementary trace elements so as to meet needs in trace elements of another specific patient.

4. The kit of any one of the preceding claims, wherein the first and, if applicable, any one of the optional second, third, fourth and/or nth supplementary unit comprises supplementary trace elements determined so as to address the specific needs of a specific patient population.

5. The kit of any one of the preceding claims, wherein the supplementary unit comprises trace elements to address the specific needs of a patient and/or patient population selected from the group consisting of:

(1) a patient suffering from systemic inflammatory response syndrome (SIRS),

(2) a patient suffering from burns;

(3) a patient undergoing continuous renal replacement therapy; and, (4) a patient living in selenium deficient areas.

6. The kit of any one of the preceding claims, wherein the basic parenteral unit comprises the following trace elements at the indicated amounts:

2-3 μg of chromium; 0-5 μg of cobalt; 0.3-0.4 mg of copper; 1.4-1.5 mg fluor; 0.5-1 mg iron; ≤ 50 μg iodine;

20-30 μg molybdenum; 40-80 μg selenium; 8-10 mg zinc; wherein the indicated amounts correspond to a daily administration dose.

7. The kit of claim 6, which comprises vanadium at ≤ 1 μg per daily administration dose.

8. The kit of any one of the preceding claims, comprising a supplementary unit for providing supplementary trace elements to a patient and/or a patient population suffering from systemic inflammatory response syndrome (SIRS), said supplementary unit comprising:

200-300 μg selenium;

5-10 mg zinc; and

10-20 μg chromium; wherein these amounts correspond to a daily administration dose of this supplementary unit.

9. The kit of any one of the preceding claims, comprising a supplementary unit for providing supplementary trace elements to a patient and/or a patient population suffering from burns, said supplementary unit comprising:

3-4 mg copper; 300-500 μg selenium; and

30-40 mg zinc; wherein these amounts correspond to a daily administration dose of this supplementary unit.

10. The kit of any one of the preceding claims, comprising a supplementary unit for providing supplementary trace elements to a patient and/or a patient population undergoing any form of continuous renal replacement therapy, said supplementary unit comprising: all the elements of the basic unit at the indicated quantities, and, in addition 100-200 μg of selenium per daily administered dose.

11. The kit of any one of the preceding claims, comprising a supplementary unit for providing supplementary trace elements to a patient and/or a patient population living in Se- deficient areas, said supplementary unit comprising 150-250 μg selenium per daily administered dose.

12. The kit of any one of the preceding claims, wherein the basic parenteral unit and any supplementary unit is provided in the form of a bag, wherein one or more bags comprising a supplementary unit may be branched to the bag of the basic parenteral unit and thereby the supplementary unit being added to the basic parenteral unit for parenteral administration together with or after or before the basic parenteral unit.

13. The kit of any one of the preceding claims, wherein any unit is substantially free of macronutrients.

14. The kit of any one of the claims 5-14, wherein a supplementary unit designed for patients of Se-defϊcient areas can be combined with one of the complementary parenteral nutritional units selected from the unit designed to patents suffering from SIRS and the unit designed for patients undergoing continued renal replacement therapy.

15. The kit according to any one of the preceding claims, wherein the patient is a critically ill patient.

16. A method of providing trace elements to patient, the method comprising the step of administrating a basic parenteral unit comprising basic trace elements, and, in dependence of a condition, a treatment and/or a geographical residence of the patient at least one further supplementary unit, wherein said supplementary unit comprises additional trace elements to meet, together with the basic unit, the specific needs in trace elements of the patient.