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Global quality assurance in parenteral nutrition
ClinicalNutrition (1995) 14:61-63 © Pearson Professional Ltd 1995
EDITORIAL
Global quality assurance in parenteral nutrition M. LATTARULO Director of Pharmacy Service and Professor of Clinical Pharmacy at the University of Bari, University Hospital of Bari, P. zza G. Cesare, 70124 Bari, Italy
A safety alert has recently been issued by the US Food and Drug Administration (FDA), 1 warning of the report by a hospital centre of two deaths and at least two cases of respiratory distress which occurred during parenteral nutrition with 'three-in-one' admixtures containing electrolytes, combined using an automated compounder. The hypothesis that the cause of the two deaths might be correlated with the formation of precipitates was confirmed at autopsy by the presence of diffuse microvascular puhnonary emboli containing calcium phosphate. Later investigations of the composition of the admixtures seem to have revealed calcium and phosphorus concentrations which are incompatible with pH conditions. The FDA warns all operators (doctors, pharmacists, nurses and patients themselves, in the case of home-administration) of the dangers of these precipitates, which can be lifethreatening. Some suggestions are made for increasing the safety of parenteral nutrient preparations while awaiting the results of further research into this complex problem. These include the following recommendations:
• During preparation (by pharmacists) and administration (by doctors, nurses and, in the case of home care, patients), beware of the formation of any precipitates. • In the case of preparations for home administration, keep a sample of the mixture in the pharmacy, under the conditions specified on the label. • Pay attention to temperatures for preservation and the relative expiry dates according to these temperatures, bearing in mind that higher temperatures may favour the formation of precipitates. • Watch out for any symptoms of acute respiratory distress, pulmonary embolism or interstitial pneumonitis during the administration of parenteral nutrient admixtures in both the hospital and home environment. The American Society of Hospital Pharmacy (ASHP) immediately published the FDA Safety Alert on its official journal, the American Journal of Hospital Pharmacy (AJHP), while in the following number, three editorials were published written by some of the most expert American hospital pharmacists in the compatibility between drugs or in artificial nutrition. In the first editorial, 2 Guy R. Hasegawa, Senior Editor of the AJHP, emphasises the importance of the pharmacist's role in ensuring that the use of drugs is not only effective but above all safe. He suggests that before this 'accident', the danger of formation of calcium phosphate salts was underestimated by many. According to Hasegawa, no other health professionals are as qualified or as obligated to effectively apply their training and experience and abundance of published data to this aspect of patient care. Lawrence A. Trissel, author of the famous Handbook on Injectable Drugs (HSHP, Bethesda), in the following editorial 3 along the same lines, points out the modern hospital pharmacist's tendency to concentrate on the clinical aspect of his activity, often neglecting that of product quality assurance. According to the author, this is also due to the traditional lack of
• Calculate the solubility of the calcium salts according to the volume to which they are added and not to the final volume, bearing in mind the phosphorus (and calcium) contents which will derive from the other components, in particular amino acid solutions. • Use 'two-in-one' admixtures (glucose and antino acids) for preference, administering the lipids by another route, since these can mask the formation of precipitates, or, when absolutely necessary, add the calcium last, just before the lipids, and inspect visually to check. • If using automated compounding devices, follow the same rules as in the preceding point as regards programming the order of filling, and adhere to any recommendations made by the manufacturer of the device. • Use filters during infusion. 61
62 EFFECTOF SUBSTRATE MANIPULATION ON REDUCING ISCHEMIA/REPERFUSIONINJURY
training received in many schools of pharmacy, lack of room in the curriculum and lack of interest among clinically oriented students and educators, where little, if any, education and training are provided for ensuring the quality of pharmacy-prepared products. Trissel considers that in the clinical environment quality assurance as correctness of therapeutic decision-making is equally important for the patient as the assurance of the quality of the products pharmacists prepare. In the third editorial,4 Jay M. Mirtallo adds some personal observations to the FDA's recommendations, in particular those on the administration of calcium separately from a TPN solution and on the use of filters during infusion of TPN solutions. In the first case he emphasises the potential risks correlated with the rapid infusion of calcium and with its high reactivity when infused through a secondary i.v. line together with the TPN admixture. He mentions the anomalous tendency to use high quantities of calcium in the normal TPN solutions. In his experience, doses of 5-7.5 mmol/day (10-15 mEq) are often sufficient and it is rarely necessary to reach 10retool/day (20 mEq). In fact, it is often enough just to correct the factors determining imbalances in the serum concentration of calcium, such as hypoalbuminaemia, excess fluids, acid-base disturbances, etc. As regards the filters, Mirtallo points out that a consensus has still not been reached on their effectiveness, particularly when weighed against the potential risks deriving from their use (potentially increased incidence of infection, breakage, infiltration of air). The FDA Safety Alert has reopened an old chapter on Artificial Nutrition which many tend to ignore. ESPEN, however, has always paid attention to this subject, guaranteeing ample space in its symposiums for discussion of the problem. An educational leaflet and some guidelines on the pharmaceutical problems of Artifical Nutrition, and in particular, of TPN, are planned for publication by ESPEN in 1995. The editorials by Hasegawa, Trissel and Mirtallo, briefly outlined above, have provided a clear commentary on the delicate problem from both the ethical and clinical points of view. Some further considerations are necessary, however. First of all, the exceptional circumstance of a warning was based on a report by a single hospital centre, although it referred two deaths and two suspected serious complications. The episode would seem to have been due to a deplorable attitude of superficiality that may represent an isolated incident. Parenteral nutrition has over 20 years of history but before this case it is usual to quote only Knowles' report published in JPEN 5 in 1989. This certainly does not mean that the problem does not exist or is not exceptionally serious. Probably in the past, and per-
haps even now, the problem has been confused with a series of other events correlated with the various different diseases affecting patients who are candidates for TPN. A second consideration is that in Europe greater experience has been acquired with 'All-in-One' admixtures than in the United States, where they still prefer separate administration of lipids. A third point which should invite reflection, however, is that, unlike in the United States, in Europe the compounding of parenteral nutrient admixtures is not conducted in pharmacies under the supervision of pharmacists in controlled environments. In many European states, in fact, due to unavailability of the pharmacists, involved in other activities which may not be consistent with their skills, these preparations are often made in infirmaries without any technicallogistic support. This is compounded by the fact that the training in clinical problems offered by European universities is virtually nonexistent, even worse than in the United States. A university specialization in Hospital Pharmacy may solve the problem in the future, but only if integration between universities and the professions is realized, in this case in particular, in the field of Clinical Pharmacy. Probably, reserving the preparation of parenteral nutrient admixtures exclusively to hospital pharmacies would not completely solve the problem, bearing in mind all that has been said above. In the United States, the American Society of Hospital Pharmacy, in collaboration with ASPEN, has begun to accredit training courses followed by examinations, specifically qualifying pharmacists to operate in the Clinical Nutrition field. Some scientific societies of clinical pharmacists are oriented in the same direction. One can but reaffirm what our expert colleagues have declared in their editorials. The recommendation to use filters could lead to a false sense of security, particularly before scientific research has resolved questions about particle size, and the potential creation of new hazards. In the same way as in the past a complete revision of the use of hypemutrition became necessary, now we must begin to think seriously about reducing high calcium regimens, except in neonatology, in which, in any case, at times of need organic sources of phosphorus can be used. To sum up, the concept of 'Global Quality Assurance' variously expressed by the three editorialists, should be the guiding spirit to health operators in all fields, not only in artificial nutrition.
References 1. Food and Drug Administartion. Safety alert: Hazards of
CLn",IICALNUTRITION 63 precipitation associated with parenteral nutrition. Am J Hosp Pharm 1994; 51: 1427-1428, 2. Hasegawa G R. Caring about stability and compatibility. Am J Hosp Pharm 1994; 51: 1533-1534. 3. Trissel L A. Compounding our problems. Am J Hosp Pharm 1994; 51: 1534.
4. Mirtallo J M. The complexity of mixing calcium and phosphate. Am J Hosp Pharm 1994; 51: 1535-1536. 5. Knowles J B, Cusson G, Smith Met al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN 1989; 13: 209-213.
EDITORIAL
Global quality assurance in parenteral nutrition M. LATTARULO Director of Pharmacy Service and Professor of Clinical Pharmacy at the University of Bari, University Hospital of Bari, P. zza G. Cesare, 70124 Bari, Italy
A safety alert has recently been issued by the US Food and Drug Administration (FDA), 1 warning of the report by a hospital centre of two deaths and at least two cases of respiratory distress which occurred during parenteral nutrition with 'three-in-one' admixtures containing electrolytes, combined using an automated compounder. The hypothesis that the cause of the two deaths might be correlated with the formation of precipitates was confirmed at autopsy by the presence of diffuse microvascular puhnonary emboli containing calcium phosphate. Later investigations of the composition of the admixtures seem to have revealed calcium and phosphorus concentrations which are incompatible with pH conditions. The FDA warns all operators (doctors, pharmacists, nurses and patients themselves, in the case of home-administration) of the dangers of these precipitates, which can be lifethreatening. Some suggestions are made for increasing the safety of parenteral nutrient preparations while awaiting the results of further research into this complex problem. These include the following recommendations:
• During preparation (by pharmacists) and administration (by doctors, nurses and, in the case of home care, patients), beware of the formation of any precipitates. • In the case of preparations for home administration, keep a sample of the mixture in the pharmacy, under the conditions specified on the label. • Pay attention to temperatures for preservation and the relative expiry dates according to these temperatures, bearing in mind that higher temperatures may favour the formation of precipitates. • Watch out for any symptoms of acute respiratory distress, pulmonary embolism or interstitial pneumonitis during the administration of parenteral nutrient admixtures in both the hospital and home environment. The American Society of Hospital Pharmacy (ASHP) immediately published the FDA Safety Alert on its official journal, the American Journal of Hospital Pharmacy (AJHP), while in the following number, three editorials were published written by some of the most expert American hospital pharmacists in the compatibility between drugs or in artificial nutrition. In the first editorial, 2 Guy R. Hasegawa, Senior Editor of the AJHP, emphasises the importance of the pharmacist's role in ensuring that the use of drugs is not only effective but above all safe. He suggests that before this 'accident', the danger of formation of calcium phosphate salts was underestimated by many. According to Hasegawa, no other health professionals are as qualified or as obligated to effectively apply their training and experience and abundance of published data to this aspect of patient care. Lawrence A. Trissel, author of the famous Handbook on Injectable Drugs (HSHP, Bethesda), in the following editorial 3 along the same lines, points out the modern hospital pharmacist's tendency to concentrate on the clinical aspect of his activity, often neglecting that of product quality assurance. According to the author, this is also due to the traditional lack of
• Calculate the solubility of the calcium salts according to the volume to which they are added and not to the final volume, bearing in mind the phosphorus (and calcium) contents which will derive from the other components, in particular amino acid solutions. • Use 'two-in-one' admixtures (glucose and antino acids) for preference, administering the lipids by another route, since these can mask the formation of precipitates, or, when absolutely necessary, add the calcium last, just before the lipids, and inspect visually to check. • If using automated compounding devices, follow the same rules as in the preceding point as regards programming the order of filling, and adhere to any recommendations made by the manufacturer of the device. • Use filters during infusion. 61
62 EFFECTOF SUBSTRATE MANIPULATION ON REDUCING ISCHEMIA/REPERFUSIONINJURY
training received in many schools of pharmacy, lack of room in the curriculum and lack of interest among clinically oriented students and educators, where little, if any, education and training are provided for ensuring the quality of pharmacy-prepared products. Trissel considers that in the clinical environment quality assurance as correctness of therapeutic decision-making is equally important for the patient as the assurance of the quality of the products pharmacists prepare. In the third editorial,4 Jay M. Mirtallo adds some personal observations to the FDA's recommendations, in particular those on the administration of calcium separately from a TPN solution and on the use of filters during infusion of TPN solutions. In the first case he emphasises the potential risks correlated with the rapid infusion of calcium and with its high reactivity when infused through a secondary i.v. line together with the TPN admixture. He mentions the anomalous tendency to use high quantities of calcium in the normal TPN solutions. In his experience, doses of 5-7.5 mmol/day (10-15 mEq) are often sufficient and it is rarely necessary to reach 10retool/day (20 mEq). In fact, it is often enough just to correct the factors determining imbalances in the serum concentration of calcium, such as hypoalbuminaemia, excess fluids, acid-base disturbances, etc. As regards the filters, Mirtallo points out that a consensus has still not been reached on their effectiveness, particularly when weighed against the potential risks deriving from their use (potentially increased incidence of infection, breakage, infiltration of air). The FDA Safety Alert has reopened an old chapter on Artificial Nutrition which many tend to ignore. ESPEN, however, has always paid attention to this subject, guaranteeing ample space in its symposiums for discussion of the problem. An educational leaflet and some guidelines on the pharmaceutical problems of Artifical Nutrition, and in particular, of TPN, are planned for publication by ESPEN in 1995. The editorials by Hasegawa, Trissel and Mirtallo, briefly outlined above, have provided a clear commentary on the delicate problem from both the ethical and clinical points of view. Some further considerations are necessary, however. First of all, the exceptional circumstance of a warning was based on a report by a single hospital centre, although it referred two deaths and two suspected serious complications. The episode would seem to have been due to a deplorable attitude of superficiality that may represent an isolated incident. Parenteral nutrition has over 20 years of history but before this case it is usual to quote only Knowles' report published in JPEN 5 in 1989. This certainly does not mean that the problem does not exist or is not exceptionally serious. Probably in the past, and per-
haps even now, the problem has been confused with a series of other events correlated with the various different diseases affecting patients who are candidates for TPN. A second consideration is that in Europe greater experience has been acquired with 'All-in-One' admixtures than in the United States, where they still prefer separate administration of lipids. A third point which should invite reflection, however, is that, unlike in the United States, in Europe the compounding of parenteral nutrient admixtures is not conducted in pharmacies under the supervision of pharmacists in controlled environments. In many European states, in fact, due to unavailability of the pharmacists, involved in other activities which may not be consistent with their skills, these preparations are often made in infirmaries without any technicallogistic support. This is compounded by the fact that the training in clinical problems offered by European universities is virtually nonexistent, even worse than in the United States. A university specialization in Hospital Pharmacy may solve the problem in the future, but only if integration between universities and the professions is realized, in this case in particular, in the field of Clinical Pharmacy. Probably, reserving the preparation of parenteral nutrient admixtures exclusively to hospital pharmacies would not completely solve the problem, bearing in mind all that has been said above. In the United States, the American Society of Hospital Pharmacy, in collaboration with ASPEN, has begun to accredit training courses followed by examinations, specifically qualifying pharmacists to operate in the Clinical Nutrition field. Some scientific societies of clinical pharmacists are oriented in the same direction. One can but reaffirm what our expert colleagues have declared in their editorials. The recommendation to use filters could lead to a false sense of security, particularly before scientific research has resolved questions about particle size, and the potential creation of new hazards. In the same way as in the past a complete revision of the use of hypemutrition became necessary, now we must begin to think seriously about reducing high calcium regimens, except in neonatology, in which, in any case, at times of need organic sources of phosphorus can be used. To sum up, the concept of 'Global Quality Assurance' variously expressed by the three editorialists, should be the guiding spirit to health operators in all fields, not only in artificial nutrition.
References 1. Food and Drug Administartion. Safety alert: Hazards of
CLn",IICALNUTRITION 63 precipitation associated with parenteral nutrition. Am J Hosp Pharm 1994; 51: 1427-1428, 2. Hasegawa G R. Caring about stability and compatibility. Am J Hosp Pharm 1994; 51: 1533-1534. 3. Trissel L A. Compounding our problems. Am J Hosp Pharm 1994; 51: 1534.
4. Mirtallo J M. The complexity of mixing calcium and phosphate. Am J Hosp Pharm 1994; 51: 1535-1536. 5. Knowles J B, Cusson G, Smith Met al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN 1989; 13: 209-213.