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Practical aspects of glutamine supplementation in theICU
132 THE OXFORD GLUTAMINE WORKSHOP Table
Gln feed Control
Results before and after feeding. Initial plasma Gin (mmol/1)
Initial muscle Gha (mmol/kg wet wt)
Final muscle Gin (mmol/kg wet wt)
Mean
SD
Mean
SD
Mean
SD
0.39 0.02
0.21 10 0.10 9
3.74 2.51
1.76 10 1.65 9
3.34 2.73
2.46 8 1.32 8
n
n
n
The initial plasma Gln was reduced in all but one of the patients biopsied (normal 0.64, CI 0.56-0.72 retool/l). The average muscle Gln content before feeding was very low (reported normal range 12.66 (SD 2.37) mmol/kg wet wt). Between biopsies no consistent pattern of change was seen with or without exogenous Gin. Intramuscular Gin in the first week of a severe illness appears unresponsive to the influence of additional Gin. However, an equal number of patients showed increases or decrease of 50% or greater in muscle Gln. This is illustrated by one septicaemic patient, Gin-supplemented, in whom muscle Gin fell from 7.17 to 1.82 mmol/1 during the study and returned to normal, 12.79 retool/l, within 2 months. Large changes in intramuscular Gln are not incompatible with a good outcome. This data indicates the demand for glutamine in these patients is tremendous during the acute illness, and while muscle Gln is initially unresponsive to nutritional support, there is a considerable nutritional debt that presumably must be repaid during convalescence. These observations should not be taken as lack of efficacy. Rather, when physiology becomes so deranged our assumptions about the utilisation of this metabolite need to change otherwise we generate false negative conclusions based upon erroneous assumptions. Although intramuscular Gln remains low and muscle protein synthesis may not be stimulated it may well be that muscle protein breakdown is reduced. Preliminary results suggest there may be a dose response effect of glutamine on muscle protein salvage. Because no two ICU patients are alike the cumulative effect of a nutritional intervention such as glutamine may not be discernible through individual short-term measures as the benefit in one patient may be different from the benefit in another. However it is worth remembering that in an ICU population with high mortality a most important indicator of benefit of L-ghitamine would be outcome measures such as survival at six months and improved quality of life. P r a c t i c a l a s p e c t s o f g l u t a m i n e s u p p l e m e n t a t i o n in t h e ICU G. Baldock, Department of Anaesthesia, HammersmithHospital, London, UK. While the results of major outcome studies are awaited, sufficient evidence of the efficacy and safety of glutamine administration in the critically-ill is available to encourage clinicians to make the benefits available to their patients. Ghitamine is, however, only one of a number of metabolic substrates that have been shown to be of benefit. The major cause of morbidity and mortality, and hence resource utilisation, in the intensive care unit (ICU) is the multiple organ dysfunction syndrome (MODS). This results from the so-called systemic inflammatory response syndrome (SIRS) which is itself a result of the host response to such diverse injurious processes as severe infection, perfusion defects (with or without reperfusion injury), trauma and pancreatitis. Inflammation is an essential part of the normal host response but if allowed to run out of control can cause severe tissue damage. Typically it is possible to identify three phases in the natural history of the condition. Phase one includes
the actual insult and initial resuscitation ('ebb phase'). The acute response starts within 24 h and peaks in 3-4 days ('flow phase') and abates by day 7-10 (recovery phase). In case of severe injury and/or compromised host death may occur quickly. Patients who survive the initial insult tend to show one of two response patterns. In one, infiammation continues and organ dysfunction develops ('stable hypermetabolism') but with aggressive corrective treatment SIRS slowly abates and the patient recovers. In the other SIRS and MODS progress inexorably and the patient dies. Characteristic metabolic responses caused by various mediators with alteration of substrate utilisation can be identified in these patients. Experimentally these responses can be modified by alterations in substrate composition. Furthermore there is, paradoxically, evidence of immuno-incompetence (notably gut-related) which may be associated with, or exacerbated by, depletion of substrates such as glutamine and other nucleic acid precursors. Another important factor is the possibility of unopposed action of damaging reactive oxygen species due to depletion of natural antioxidant mechanisms. Management of SIRS and MODS involves control of the source of the insult, adequate resuscitation and metabolic/nutritional support. All these aspects of treatment are of equal importance must be simultaneously and vigorously applied during all phases of the evolution of the syndromes. Early enteral feeding has been shown to be of benefit in patients with severe traumatic, bum and surgical injury. All critically-ill patients are at risk of certain micro-nutrient deficiencies, notably of folate, thiamine and vitamin E. The benefit of nutritional support is not so much in the restoration of nitrogen balance and preservation of body mass (which is almost impossible in the hypermetabolic patient) but in modulating various host defence mechanisms, particularly the anti-oxidant complex, cytoklne production, arachidonic acid metabolism, and the cells of the gut mucosa and immune system. The limitations of standard nutritional formulae (both enteral and particularly parenteral) in the latter functions have led to the introduction of so-called 'novel' (but actually probably more correctly 'rediscovered') substrates, like glutamine. It is possible on the basis of current evidence to hypothesize that priorities in metabolic support should change during the evolution of SIRS and MODS. On admission to ICU, at which time the patient will still be in the 'ebb phase', the priority is to correct possible micro-nutrient deficiencies and support the various anti-oxidant mechanisms which may be stressed by sepsis and/or ischaemia/reperfusion. As the patient enters the early 'flow phase' between 8 and 24 h the priority is to support the immune system with appropriate macro-nutrients via the enteral route where possible. If glutamine is to be used it should be administered early because studies have shown that glutamine depletion occurs early and is difficult to reverse once established. Total parenteral nutrition (TPN) may be harmful during the early 'flow phase' and if enteral feeding is not possible (or fails) TPN should probably be postponed for two or three days. Intravenous administration of glutamine alone is safe and may be beneficial. In the late 'flow phase' and during recovery or stable hypermetabolism priority shifts to establishing full nutritional support appropriate to metabolic rate and nitrogen loss. Addition of glutamine and other substrates to conventional feeds (enteral and parenteral) may be of continuing benefit. The commercial availability of special enteral feeds makes it practicable to give glutamine supplements to most patients in the ICU from soon after admission. The main limitation is the instability of glutamine in solution which means that such feeds are supplied in powder form and have to be mixed with water prior to use. This is an extra burden on the ICU nursing staff and also requires scrupulous attention to cleanliness to minimise the risk of contamination. These feeds are also somewhat more expensive than
CLINICAL NUTRITION 133 standard formulas but in the context of the overall cost of caring for patients in ICU the increase in expenditure is marginal and may be offset by benefits such as fewer complications and shorter stay. For those patients who cannot be enterally fed a preparation of glutamine solution suitable for intravenous infusion is required. Glutamine is relatively insoluble and is supplied as a 2.5% solution. The dose used (20 g/day) thus requires 800 ml of solution which when administered alone is unlikely to cause problems with fluid balance but may be a problem as part of TPN regimen in patients who need to be fluid restricted. The commercial preparation is supplied frozen and even when thawed is stable for some time if kept cool. It is therefore feasible to keep a small supply of glutamine solution refrigerated on the ICU for immediate use with back up from the frozen supply in the pharmacy. Again the cost is not great in view of the possible ber/efits. In conclusion, with a little ingenuity, careful planning and the expenditure of a little extra in resources and effort it is quite possible to provide glntamine supplementation for all patients within 24 h of admission to the ICU. C l i n i c a l experience using a g l u t a m i n e enriched feed S. Schenker a n d G. Hardy, Oxford Nutrition Ltd, P 0 Box 31E,
Oxford OX3 3UH, UK
Introduction The theoretical need for glutamine supplementation in critically-ill patients is well documented. Glutamine is increasingly being considered a conditionally essential amino acid in times of metabolic stress (1). However, as yet there is little actual clinical data supporting its use in such patients. Indeed, no specific patient criteria have been identified so policies on its use cannot be made. Clinical benefits of glutamine supplemented TPN associated with chemotherapy or whole body irradiation prior to bone marrow transplantation include an improvement in nitrogen balance, protection from an expansion of the extracellular fluid compartment, a diminished incidence of infection and a shortened hospital stay (2, 3). These findings were then repeated by Schloerb and Amare (4). Hammarqvist et al (5) administered glntamine supplemented TPN post-operatively to patients undergoing elective abdominal surgery with no adverse effects. These patients exhibited an improvement in nitrogen balance and a sparing of the intramuscular glutamine pool. Less work has been undertaken on enteral feeding regimens supplemented with glutamine. Gottschilch et al (6) employed a glutamine enriched enteral feed for the treatment of burns patients. The study confirmed low plasma glntamine concentrations in bums injury, but fell short of demonstrating any positive beneficial effects. While the clinician needs to decide whether the case is yet made for the routine use of glutamine, commercial enteral formulae enriched with this amino acid are now currently available.
Aim It was the aim of this pilot study to evaluate dietetic and nursing opinion on the practical and clinical aspects of administering such a feed (Protina G, Torre Farmaceutici, Italy).
Method A 12 point questionnaire was used to interview various health care professionals responsible for using the feed (either as prescribers or administrators) from four hospitals (two teaching hospitals and two district hospitals). The feed is nutritionally complete, in whole protein form, enriched with free L-glutamine. It is supplied as a freeze-dried powder, in a bottle, to which sterile water is added and easily dissolves into a feed ready for use. After reconstitution, if the feed is not used immediately it may be kept refrigerated for up to 24 h.
Once in use it has a recommended hanging time of 6-8 h. The feed was only administered to patients in the intensive care unit.
Results A total of 50 critically-ill patients were evaluated. Patients were of both sexes and ages ranged from 17-59 years. Feeding regimens varied, although the majority of patients (78%) started on the glutamine enriched feed immediately. This left 22% of patients that were fed more selectively; initially with a standard enteral formula before changing to the glutamine feed. In some cases the glutamine feed was commenced 3-4 days later, in others it was not used for a number of weeks. Both route of feeding and administration of the feed varied. The preferred feeding route was naso-gastric (68%) and most regimens were continuous over 24 h providing 30-40 kcal per kg body weight. Other feeding routes included gastrostomy feeding (25%) and naso-jejunal feeding (7%). In all cases nutritional requirements were calculated from standard formulae based on various stress factors. Feeding administration ranged from < 20 kcal to > 40 kcal per kg body weight. Patients were monitored using standard biochemical and anthropometric measurements. Nitrogen balance was determined in 18% of patients and in all instances improved with use of the glutamine feed. All patients tolerated the feed and in some cases the feed actually helped prevent further diarrhoea when this had previously been a problem with a standard formula. No side-effects were reported and nursing comments on reconstituting the feed and ease of use were positive. One remarkable observation was seen in patients requiring respiratory support. All hospitals reported that the provision of the glutamine enriched feed aided the patient in coming off the ventilator.
Discussion It is notable that all methods of patient monitoring, biochemical and anthropometric, fell in line with national trends, as measured by Payne-James et al (7) in the second national survey of artificial nutrition support in UK hospitals. It is well documented that early enteral feeding is beneficial in the prevention of diarrhoea and that the provision of the feed as a whole protein formula rather than an elemental formula is better tolerated. The provision of glutamine has been associated with a decreased risk of bacterial translocation of the gut by a number of authors (8, 9). Together these factors must be of some significance to the good tolerance that was observed in all patients, and also the improved tolerance that was seen when patients changed from a standard formula to the glutamine enriched feed. Both Souba et al (9) and Welbourne (10) report that the lung is a major site of glutamine synthesis as it contains the necessary enzyme glutamine synthetase. Lung glutamine exchange during critical illness has not been studied, however, recent data from animal studies suggest that the lungs play a key role in glutamine flow in both normal and catabolic states (9). This may then have some association with the observation (however anecdotal) that the provision of glutamine facilitated the transition of patients off respiratory support. The positive comments from nursing staff on the practicalities of using a glutamine enriched feed are encouraging. It is important to note, however, that the addition of glutamine to an enteral feed makes it a prime target for bacterial colonization, therefore, strict adherence to reconstituting methods and hanging times must be enforced.
Conclusion It is concluded that in light of recent evidence from controlled clinical trials and these positive experiences that further trials are
Gln feed Control
Results before and after feeding. Initial plasma Gin (mmol/1)
Initial muscle Gha (mmol/kg wet wt)
Final muscle Gin (mmol/kg wet wt)
Mean
SD
Mean
SD
Mean
SD
0.39 0.02
0.21 10 0.10 9
3.74 2.51
1.76 10 1.65 9
3.34 2.73
2.46 8 1.32 8
n
n
n
The initial plasma Gln was reduced in all but one of the patients biopsied (normal 0.64, CI 0.56-0.72 retool/l). The average muscle Gln content before feeding was very low (reported normal range 12.66 (SD 2.37) mmol/kg wet wt). Between biopsies no consistent pattern of change was seen with or without exogenous Gin. Intramuscular Gin in the first week of a severe illness appears unresponsive to the influence of additional Gin. However, an equal number of patients showed increases or decrease of 50% or greater in muscle Gln. This is illustrated by one septicaemic patient, Gin-supplemented, in whom muscle Gin fell from 7.17 to 1.82 mmol/1 during the study and returned to normal, 12.79 retool/l, within 2 months. Large changes in intramuscular Gln are not incompatible with a good outcome. This data indicates the demand for glutamine in these patients is tremendous during the acute illness, and while muscle Gln is initially unresponsive to nutritional support, there is a considerable nutritional debt that presumably must be repaid during convalescence. These observations should not be taken as lack of efficacy. Rather, when physiology becomes so deranged our assumptions about the utilisation of this metabolite need to change otherwise we generate false negative conclusions based upon erroneous assumptions. Although intramuscular Gln remains low and muscle protein synthesis may not be stimulated it may well be that muscle protein breakdown is reduced. Preliminary results suggest there may be a dose response effect of glutamine on muscle protein salvage. Because no two ICU patients are alike the cumulative effect of a nutritional intervention such as glutamine may not be discernible through individual short-term measures as the benefit in one patient may be different from the benefit in another. However it is worth remembering that in an ICU population with high mortality a most important indicator of benefit of L-ghitamine would be outcome measures such as survival at six months and improved quality of life. P r a c t i c a l a s p e c t s o f g l u t a m i n e s u p p l e m e n t a t i o n in t h e ICU G. Baldock, Department of Anaesthesia, HammersmithHospital, London, UK. While the results of major outcome studies are awaited, sufficient evidence of the efficacy and safety of glutamine administration in the critically-ill is available to encourage clinicians to make the benefits available to their patients. Ghitamine is, however, only one of a number of metabolic substrates that have been shown to be of benefit. The major cause of morbidity and mortality, and hence resource utilisation, in the intensive care unit (ICU) is the multiple organ dysfunction syndrome (MODS). This results from the so-called systemic inflammatory response syndrome (SIRS) which is itself a result of the host response to such diverse injurious processes as severe infection, perfusion defects (with or without reperfusion injury), trauma and pancreatitis. Inflammation is an essential part of the normal host response but if allowed to run out of control can cause severe tissue damage. Typically it is possible to identify three phases in the natural history of the condition. Phase one includes
the actual insult and initial resuscitation ('ebb phase'). The acute response starts within 24 h and peaks in 3-4 days ('flow phase') and abates by day 7-10 (recovery phase). In case of severe injury and/or compromised host death may occur quickly. Patients who survive the initial insult tend to show one of two response patterns. In one, infiammation continues and organ dysfunction develops ('stable hypermetabolism') but with aggressive corrective treatment SIRS slowly abates and the patient recovers. In the other SIRS and MODS progress inexorably and the patient dies. Characteristic metabolic responses caused by various mediators with alteration of substrate utilisation can be identified in these patients. Experimentally these responses can be modified by alterations in substrate composition. Furthermore there is, paradoxically, evidence of immuno-incompetence (notably gut-related) which may be associated with, or exacerbated by, depletion of substrates such as glutamine and other nucleic acid precursors. Another important factor is the possibility of unopposed action of damaging reactive oxygen species due to depletion of natural antioxidant mechanisms. Management of SIRS and MODS involves control of the source of the insult, adequate resuscitation and metabolic/nutritional support. All these aspects of treatment are of equal importance must be simultaneously and vigorously applied during all phases of the evolution of the syndromes. Early enteral feeding has been shown to be of benefit in patients with severe traumatic, bum and surgical injury. All critically-ill patients are at risk of certain micro-nutrient deficiencies, notably of folate, thiamine and vitamin E. The benefit of nutritional support is not so much in the restoration of nitrogen balance and preservation of body mass (which is almost impossible in the hypermetabolic patient) but in modulating various host defence mechanisms, particularly the anti-oxidant complex, cytoklne production, arachidonic acid metabolism, and the cells of the gut mucosa and immune system. The limitations of standard nutritional formulae (both enteral and particularly parenteral) in the latter functions have led to the introduction of so-called 'novel' (but actually probably more correctly 'rediscovered') substrates, like glutamine. It is possible on the basis of current evidence to hypothesize that priorities in metabolic support should change during the evolution of SIRS and MODS. On admission to ICU, at which time the patient will still be in the 'ebb phase', the priority is to correct possible micro-nutrient deficiencies and support the various anti-oxidant mechanisms which may be stressed by sepsis and/or ischaemia/reperfusion. As the patient enters the early 'flow phase' between 8 and 24 h the priority is to support the immune system with appropriate macro-nutrients via the enteral route where possible. If glutamine is to be used it should be administered early because studies have shown that glutamine depletion occurs early and is difficult to reverse once established. Total parenteral nutrition (TPN) may be harmful during the early 'flow phase' and if enteral feeding is not possible (or fails) TPN should probably be postponed for two or three days. Intravenous administration of glutamine alone is safe and may be beneficial. In the late 'flow phase' and during recovery or stable hypermetabolism priority shifts to establishing full nutritional support appropriate to metabolic rate and nitrogen loss. Addition of glutamine and other substrates to conventional feeds (enteral and parenteral) may be of continuing benefit. The commercial availability of special enteral feeds makes it practicable to give glutamine supplements to most patients in the ICU from soon after admission. The main limitation is the instability of glutamine in solution which means that such feeds are supplied in powder form and have to be mixed with water prior to use. This is an extra burden on the ICU nursing staff and also requires scrupulous attention to cleanliness to minimise the risk of contamination. These feeds are also somewhat more expensive than
CLINICAL NUTRITION 133 standard formulas but in the context of the overall cost of caring for patients in ICU the increase in expenditure is marginal and may be offset by benefits such as fewer complications and shorter stay. For those patients who cannot be enterally fed a preparation of glutamine solution suitable for intravenous infusion is required. Glutamine is relatively insoluble and is supplied as a 2.5% solution. The dose used (20 g/day) thus requires 800 ml of solution which when administered alone is unlikely to cause problems with fluid balance but may be a problem as part of TPN regimen in patients who need to be fluid restricted. The commercial preparation is supplied frozen and even when thawed is stable for some time if kept cool. It is therefore feasible to keep a small supply of glutamine solution refrigerated on the ICU for immediate use with back up from the frozen supply in the pharmacy. Again the cost is not great in view of the possible ber/efits. In conclusion, with a little ingenuity, careful planning and the expenditure of a little extra in resources and effort it is quite possible to provide glntamine supplementation for all patients within 24 h of admission to the ICU. C l i n i c a l experience using a g l u t a m i n e enriched feed S. Schenker a n d G. Hardy, Oxford Nutrition Ltd, P 0 Box 31E,
Oxford OX3 3UH, UK
Introduction The theoretical need for glutamine supplementation in critically-ill patients is well documented. Glutamine is increasingly being considered a conditionally essential amino acid in times of metabolic stress (1). However, as yet there is little actual clinical data supporting its use in such patients. Indeed, no specific patient criteria have been identified so policies on its use cannot be made. Clinical benefits of glutamine supplemented TPN associated with chemotherapy or whole body irradiation prior to bone marrow transplantation include an improvement in nitrogen balance, protection from an expansion of the extracellular fluid compartment, a diminished incidence of infection and a shortened hospital stay (2, 3). These findings were then repeated by Schloerb and Amare (4). Hammarqvist et al (5) administered glntamine supplemented TPN post-operatively to patients undergoing elective abdominal surgery with no adverse effects. These patients exhibited an improvement in nitrogen balance and a sparing of the intramuscular glutamine pool. Less work has been undertaken on enteral feeding regimens supplemented with glutamine. Gottschilch et al (6) employed a glutamine enriched enteral feed for the treatment of burns patients. The study confirmed low plasma glntamine concentrations in bums injury, but fell short of demonstrating any positive beneficial effects. While the clinician needs to decide whether the case is yet made for the routine use of glutamine, commercial enteral formulae enriched with this amino acid are now currently available.
Aim It was the aim of this pilot study to evaluate dietetic and nursing opinion on the practical and clinical aspects of administering such a feed (Protina G, Torre Farmaceutici, Italy).
Method A 12 point questionnaire was used to interview various health care professionals responsible for using the feed (either as prescribers or administrators) from four hospitals (two teaching hospitals and two district hospitals). The feed is nutritionally complete, in whole protein form, enriched with free L-glutamine. It is supplied as a freeze-dried powder, in a bottle, to which sterile water is added and easily dissolves into a feed ready for use. After reconstitution, if the feed is not used immediately it may be kept refrigerated for up to 24 h.
Once in use it has a recommended hanging time of 6-8 h. The feed was only administered to patients in the intensive care unit.
Results A total of 50 critically-ill patients were evaluated. Patients were of both sexes and ages ranged from 17-59 years. Feeding regimens varied, although the majority of patients (78%) started on the glutamine enriched feed immediately. This left 22% of patients that were fed more selectively; initially with a standard enteral formula before changing to the glutamine feed. In some cases the glutamine feed was commenced 3-4 days later, in others it was not used for a number of weeks. Both route of feeding and administration of the feed varied. The preferred feeding route was naso-gastric (68%) and most regimens were continuous over 24 h providing 30-40 kcal per kg body weight. Other feeding routes included gastrostomy feeding (25%) and naso-jejunal feeding (7%). In all cases nutritional requirements were calculated from standard formulae based on various stress factors. Feeding administration ranged from < 20 kcal to > 40 kcal per kg body weight. Patients were monitored using standard biochemical and anthropometric measurements. Nitrogen balance was determined in 18% of patients and in all instances improved with use of the glutamine feed. All patients tolerated the feed and in some cases the feed actually helped prevent further diarrhoea when this had previously been a problem with a standard formula. No side-effects were reported and nursing comments on reconstituting the feed and ease of use were positive. One remarkable observation was seen in patients requiring respiratory support. All hospitals reported that the provision of the glutamine enriched feed aided the patient in coming off the ventilator.
Discussion It is notable that all methods of patient monitoring, biochemical and anthropometric, fell in line with national trends, as measured by Payne-James et al (7) in the second national survey of artificial nutrition support in UK hospitals. It is well documented that early enteral feeding is beneficial in the prevention of diarrhoea and that the provision of the feed as a whole protein formula rather than an elemental formula is better tolerated. The provision of glutamine has been associated with a decreased risk of bacterial translocation of the gut by a number of authors (8, 9). Together these factors must be of some significance to the good tolerance that was observed in all patients, and also the improved tolerance that was seen when patients changed from a standard formula to the glutamine enriched feed. Both Souba et al (9) and Welbourne (10) report that the lung is a major site of glutamine synthesis as it contains the necessary enzyme glutamine synthetase. Lung glutamine exchange during critical illness has not been studied, however, recent data from animal studies suggest that the lungs play a key role in glutamine flow in both normal and catabolic states (9). This may then have some association with the observation (however anecdotal) that the provision of glutamine facilitated the transition of patients off respiratory support. The positive comments from nursing staff on the practicalities of using a glutamine enriched feed are encouraging. It is important to note, however, that the addition of glutamine to an enteral feed makes it a prime target for bacterial colonization, therefore, strict adherence to reconstituting methods and hanging times must be enforced.
Conclusion It is concluded that in light of recent evidence from controlled clinical trials and these positive experiences that further trials are