.
`
`Iv! ::JJtl,;A UL.
`
`~
`
`ConferencE~
`on Netritio1r1
`and
`Cancer Theratpy
`
`Miltenyi Ex. 1026 Page 1
`
`

`

`PROGRAM PLANNING COMMITTEE
`Honor8ry ChBirman
`Jonathan E. Rhoads
`
`Giovanni Costa
`Vincent T. DeVita, Jr.
`William D. DeWys
`
`Glo B. Gori
`
`Co-Chairmen
`LaSalle 0. Le1~all, Jr.
`
`Committee Members
`Stanley J. Oudrick
`Jimmie C. B. Holland
`Arthur I. Holleb
`Walter Lawrence, Jr.
`
`American Cancer Society Staff
`Lee Kanwisher
`
`Jack W. Milder
`Maurice E. Shils
`Stefano Vivona
`
`PROGRAM
`List of Participants . . ......... ..... ....... .... . ... . .. • • • • • • . • • • • • • • • • · · · · · .. · · · ·
`· · · · · • • • • . . . . . . . 232◄
`Foreword: Conference on Nutrition and Cancer Therapy
`Jack W. Milder ....... . .. .. ..................... .... . • • • • • • • • • • • • • · · · · · · · · • · • · · • · · · · · • · · · · · • • • • • . . . .. . . 2325
`Welcome Address: Conference on Nutrition and Cancer Therapy
`Jonathan E. Rhoads ..... ...... ..... - - - -- .. ....... . ....... • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · • • • • • • • . . . . . . . . 2326
`
`SESSION I
`General Effects of Cancer on Nutrition
`
`Chairman: Giovanni Costa
`
`Cachexia, the Metabolic Component of Neoplastic Diseases.
`Giov9nni Costa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . . . . . • . . • . . . . . . . . . . . . . . . . . . . . . . . 2327
`Energy Metabolism and Requirements in the Cancer Patient.
`Vernon R. Young .. . . .. . ... . . ...... . . .. .................................. ... ................... .... .... 2336
`The Effect of Cancer on Nitrogen, Electrolyte, and Mineral Metabolism.
`George L. Blackburn, Balle/ S. Maini, Bruce R. Bistrian, and William V. McDermott, Jr . ....•.............. 2348
`Anorexia in Cancer Patients.
`William D . DeWys .... .. . ... ...... ........ ... ...... . ...... .. ......... . . . .... .. . ... .... .... . ............ 23S4
`Uncomplicated Starvation versus Cancer Cachexia.
`Murray F. Brennan ..... .. . ............................... ... ........ . ..... _ ... ... .... . •... . ....... .. .. 2359
`Summary of the Informal Discussion of General Effects of Cancer on Nutrition.
`Giovanni Costa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . • . . . . . . • . .. . . 2365
`
`Impaired Organ System Effects of Cancer on Nutrition
`
`Chairman: LaSalle D. Leffall, Jr.
`
`Nutritional Problems Associated with Gastrointestinal and Genitourinary Cancer.
`Maurice E. Shits .......... ... ......... .... ...... .. - - .. .... • • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · • · · · · · · · · · ·
`Effects of Cancers of the Endocrine and Central Nervous Systems on Nutritional Status.
`Mortimer B. Lipsett , ........ . . . .. .... . ........... .. - - ... , • • - • • • - - · • • · · · · · · · - · · · · · · · · · · · · · · · · · · · · · · · · · · ·
`Summary of the Informal Discussion of Impaired Organ System Effects o1' Cancer on Nutrition.
`LaSalle D. Le/fall, Jr . ......................................... .. ... ... ......... ....... . • • • • • • · · · · · · · · · ·
`
`2366
`
`2373
`
`2377
`
`2322
`
`CANCER RESEARCH VOL JI
`
`Miltenyi Ex. 1026 Page 2
`
`

`

`SESSION II
`Nutritional Consequences of Therapy
`
`Chairman: Walter Lawrence, Jr.
`
`•iional Consequences of Surgical Resection of the Gastrointestinal Tract for Cancer
`Nutn Walter Lawrence, Jr.. ... .... .. ...
`. . .. .. .. .
`. ....... . .'. ... . ...
`·
`eHeCIS on Nutrition of Surgery of the Live r, Pancreas, and Genitourinary Tract.
`Maurice E. Shits. . ...... .
`.. . .. . . .. .. .. .. .
`. . ..... ..
`trilional Consequences of Cancer Chemotherapy and lmmunotherapy.
`Nu Takao Ohnuma and James F. Holland .. . .. . .
`.. ........... . ... . .......... . . .. . . .
`Nutrilional Consequences of Radiotherapy.
`. . . ..
`. . . . . . . . . .
`Sarah S. Donaldson . . . . . . . . . . . . . . . . . . . .
`summary of the Informal Discussion of Nutritional Consequences of Therapy.
`Walter Lawrence, Jr. . . . . . . . .
`. .... . . .. . .. .. . . .. . ......... . ..... . .. . . ........ . .. .
`
`2379
`
`2387
`
`2395
`
`2407
`
`2414
`
`Nutritional Management- Part I
`
`Chairman: Stanley J. Dudrick
`
`0etermination of Nutritional Needs.
`Giovanni Costa ................ .
`
`.. .. 2419
`
`SESSION Ill
`Nutritional Management- Part II
`
`Chairman: Stanley J . Dudrick
`
`psychological Aspects of Anorexia in Cancer Patients.
`Jimmie C. 8. Holland, Julia Rowland, and Mar;orie Plumb
`Oral Feeding in the Nutritional Management of the Cancer Patient.
`William D. DeWys and Susan Hillenbrand Herbst ..
`Enleral Nutrition by Tube.
`Maurice E. Shils . . . ..... .
`Parenteral Nutrition Techniques in Cancer Patients.
`Stanley J. Dudrick, Bruce V. MacFadyen, Jr., Eduardo A. Souchon, DeAnn M. Englert, and Edward M.
`Copeland, II I
`. ... . ... . . .. .. ... . . . . ........................ . . . .. . . . . .. . . . . .. . .. . ......... . ... . .. .
`Nutrition as an Adjunct to Cancer Treatment in the Adult.
`Edward M. Copeland, Ill, John M. Daly, and Stanley J . Dudrick . ... • .
`Nutritional Therapy in Children with Cancer.
`Jan van Eys .
`. .. ... ... .......... .. .... . .. . . ........ .
`Summary of the Informal Discussion of Nutritional Management.
`Stanley J. Dud rick ...... .. ..... , .. .. .. .. ... .. • • • • • •
`· · .. · .. .... • .... • • .. · • • · · · · · · .. · · · · · · · · · · · · · · ·
`
`2425
`
`2429
`
`2432
`
`2440
`
`2451
`
`2457
`
`2462
`
`Summalion: Conference on Nutrition and Cancer Therapy.
`· · · · · · · · · · · • · · · . ... .... .. . . ... . . . . .... . ·· • · . . • . · · • ·· · • ·· ··· 2469
`Gio 8 . Gori . . . . . . . . .
`
`JiJLY 1977
`
`2323
`
`Miltenyi Ex. 1026 Page 3
`
`

`

`(CANCER RESEARCH 37, 24Ml-2"50, July 1977)
`
`Parenteral Nutrition Techniques in Canc1er Patients1
`
`Stanley J. Dudrlck,' Bruce v . MacFadyen, Jr., Eduardo A. Souchon, OeAnn M. Englert, and Edward M
`Copeland, 111
`.
`Oepanment of Surgt ry {S. J. o., B. v. M .. E. A. s .. E. M. C.J, Tht untv&rslty 01 Texu Medical School st Housfon, The UnMlrslty of Te,cas Syarem C,nc:e,
`Center. M. 0. Anderson Hospital end Tumor Institute, snd Hermann HospiUtllThe University Ho.spital /D.M.E.J, Houston, Tt KH 77030
`
`Summary
`
`If a patient is expected to respond optimally to one or
`more forms of oncologic therapy, he should simultaneously
`be in the best possible nutritional and metabolic condition.
`When the alimentary tract cannot be used effectively for
`feeding cancer patients, parenteral nutrition can be lifesav(cid:173)
`ing. Moreover, patients who are poor candidates or non(cid:173)
`candidates for any antineoplastic therapy because of their
`debility or cachexia can be converted to reasonable candi(cid:173)
`dates following a course of i.v. hyperalimentation. This i.v.
`hyperalimentation can significantly reduce the morbidity
`and mortality of cancer patients without stimulating tumor
`growth when applied conscientiously according to the es(cid:173)
`tablished principles and techniques and when integrated
`with specific tumor therapy.
`With the use of ambulatory or home hyperalimentation
`techniques, normal nutritional status can be restored or
`maintained during prolonged periods of antineoplastic
`therapy on a practical and relatively economical outpatient
`basis. It is anticipated that specific nutrient substrate for(cid:173)
`mulas and parenteral therapy techniques will be developed
`to maintain optimal host nutrition while adversely affecting
`the neoplasm.
`
`Introduction
`
`Nutrient substrates are required by the human body in
`sufficient quantity and of adequate quality to supply basal
`metabolic needs and to support a state of nutritional equi(cid:173)
`librium and positive nitrogen balance under a wide variety
`of conditions associated with catabolism. Moreover, re(cid:173)
`quirements can be significantly accentuated by major
`trauma, burns, sepsis, metabolic disorders and, possibly,
`malignant diseases. For many years it has been postulated
`that metabolic demands are increased in patients with ma(cid:173)
`lignant neoplasms. but this has never been clearly docu(cid:173)
`mented. When the diagnosis of cancer is made initially,
`patients are usually adequately nourished. However, var(cid:173)
`ious forms of effective antineoplastic therapy often result in
`severe nutritional deficits and are associated with weight
`loss, protein malnutrition, and inanition. On the other hand,
`loss of body mass can be the initial clinical sign in patients
`with specific cancers such as leukemia,'lymphoma, and oat
`
`1 Presented at the Conference on Nutrition and Cancer Therapy, Novem•
`ber 29 to Oeoember 1, 1976, Key Biscayne, Fla.
`-a To whom requests for reprinls should be addressed, at Department of
`Surgery, The University of Texas Medical School, 6400 West Cullen Streel,
`Houston. Tex.as n030.
`
`cell carcinoma of the lung. In such patients, tumor bulk can
`achieve rathnr large proportions before symptoms become
`manifest, am:I weight loss may ,n part reflect ttie increased
`nutritional domands imposed upon the host by the progres(cid:173)
`sive tumor t,urden. Conversely, breast cancer, malignant
`melanoma, nnost soft tissue sarcomas, and the majority of
`gastrointesti,nal cancers produce early signs and symptoms
`(such as blee,ding or a palpable mass) while the tumor mass
`is relatively ,small, and any weight loss secondary to the
`demands of the neoplasm can be identified or appreciated.
`Some specific alimentary tract cancers, particularly those of
`the oropharynx and esophagus, induce weight loss because
`of reduced 1p.o. intake secondary to obstruction or dys(cid:173)
`phagia. Simi larly, lymphoma of the small bowel and certain
`hormone-secreting tumors, such as carcinoma of the pan(cid:173)
`creatic islet cells, can result in malnutrition secondary to
`malabsorptic,n. Nevertheless. the malnutrition seen in pa(cid:173)
`tients with cancer is usually iatrogenic as a resull of onco(cid:173)
`logical thera,py, unless the patient has neglected his symp(cid:173)
`toms for sevoral months and has become cachectic second(cid:173)
`ary to dimini,shed p.o. intake and increased tumor mass.
`During onc:ological treatment, malnutrition and inanltlon
`can be preve•nted, minimized, or corrected by the appropri(cid:173)
`ate use of currently available i.v. and enteral nutrient regi(cid:173)
`mens. Whenever possible, the gastrointestinal tract should
`be utilized for digestion, absorption, and assimilation of
`nutrients. The most natural and practical method of nutrient
`administration is p.o., and the next most feasible method of
`nutrient delivery is via nasogastric or nasoduodenal feeding
`tubes. However, operative insertion of a gastrostomy or
`jejunostomy tube may be necessary for long-term nutri(cid:173)
`tional maintonance in some patients. Unfortunately, optimal
`nutritional rohabilitation via the alimentary tract can require
`an inordinate amount of time, and specific antineoplastic
`therapy cannot always be deferred until protein and energy
`stores have been replenished adequately by this route.
`During tho past decade, IVH' has become available to the
`oncologist as a safe, effective, and practical method of
`nutritional r•ehabilitation. The concept of concentrated i.v.
`nutrients to meet the high caloric and protein requirements
`of critically ill patients was originally tested in 1966 (6). In
`the initial experiment, beagle puppies fed exclusively by
`vein with a 30% nutrient solution consisting primarily of
`glucose and protein hydrolysates via the superior vena cava
`grew and d•~veloped normally for periods up to 9 months.
`Following tlhis experience the technique of IVH was suc(cid:173)
`cessfully ad,apted for use in pediatric and adult humans (7}.
`
`1 The abbre~i atlon u.sed is: IVH. i .v. hyperalimentation.
`
`2440
`
`CANCER RESEARCH VOL- 37
`
`Miltenyi Ex. 1026 Page 4
`
`

`

`.,
`
`,.1though ~ any indl~i_dual patients with malignant disor(cid:173)
`ders ha~ received nutritional s~pport via parenteral hyperal(cid:173)
`imentatIon, extensive app lications of this technique to the
`nutrftlonal rehabilitation of cancer patients in a prospective
`,unlcal study were pioneered at the M. o. Anderson Hospi(cid:173)
`tal and Tumor t_nstltu~e (4). Since the hyperalimentation
`tf1111 was established m 1972. more than 2000 patients •
`our series have received IVH as a means of nutritlo in,
`na
`.
`t.
`t
`maintenance or_ res ora 10n prior to, during, and/or follow-
`1119 treatment with c hemotherapy, radiotherapy, or surg
`eecause of _lVH, the gastrointe_stinal tract can be bypas:Zi
`and rested m a basal state while p~sitive nitrogen balance
`and astate of anabolism can be attained within 7 to 10 d
`n,Js technique o f total parenteral nutrition has proven I ai;,s.
`safe and effective, and stimulation of tumor growth has°no~
`been observed as a consequence of the i.v . feeding .
`A rational approach to n utritional rehabilitation Is to re(cid:173)
`p1tnish the cancer patient rapidly, using JVH until the ali(cid:173)
`,nenla':' tract_ can be u~ effectively. The patient can be
`,nalntaoned ~•th a chem1caUy defined diet or other accepta(cid:173)
`ble form~lat1on until Ingestion, digestion, absorption. and
`assimllat1on of adequate quantities of normal foodstuffs are
`possible enteraliy.
`The purpose of this paper is to describe and discuss the
`composition and preparation of IVH solutions; the tech(cid:173)
`nique of ce~tral venous catheter Insertion and long-term
`catheter maintenance; the principles of IVH administration
`and patient monitoring; the prevention, recognition. and
`management of complications during IVH therapy; the Insti(cid:173)
`tution of an IVH team; and the applicatlon of ambulatory or
`home hyperalimentation.
`
`Composition and Preparation ol the Nutrie nt Sotullon
`
`IVH solutions prepared in our institutions are quite hyper(cid:173)
`Ionlc, having an osmolarity of 1800 to 2400 mOsmoles/liter.
`They are admixed In the pharmacy under laminar-flow, Iii·
`teted-alr hoods, either by mixing 500 ml of 50% dextrose
`wilh 500 ml of an 8.5% crystalline amino acid solution or by
`mixing 350 ml of 50% dextrose with 750 ml of 5 to 10%
`protein hydrolysate In 5% dextrose. Such solutions provide
`approximately 1000 Cal per liter and between 5.25 and 10.0
`g of nitrogen per liter. Electrolytes and vitamins must be
`added to these base solutions in appropriate dosages to
`salisfy dally requirements. Although the protein hydrolysate
`solutions (casein or fibrin based) contain various electro(cid:173)
`lytes and trace element s as contaminants of their process•
`Ing and storage in glass containers, the major electrolytes
`must be added to these solutions prior to infusion . The
`usual electrolyte additives to the hypertonlc nutrient mix·
`tures derived from the protein hydrolysate solutions Include
`approximately 40 to 50 mEq sodium chloride, 20 to 40 mEq
`P0tasslum chloride, 10 to 15 mEq magnesium sulfate and 15
`to20 mEq potassium acid phosphate per liter. Although the
`tasein hydrolysates that are prepared by the enzymatic
`hydrolysis of the phosphoprotein casein contain large
`imounts of phosphorus (20 to 40 mmoles/liter), the phos(cid:173)
`Phorus apparently Is bound to the peptides and/or amino
`acids In such a manner as to be neither available nor eftec•
`live in maintaining normal serum phosphorus concentra·
`
`Parenteral Nutrition
`
`lions. Indeed, the 1st reported occurrence of hypophospha(cid:173)
`temla during hyperallmentation was In a patient recel~lng
`casein hydrolysate as the nitrogen source. Fibrin hydro ly(cid:173)
`s_ate, prepared by the acid hydrolysis of bovine or porcine
`~~".n: contains no significant amounts of phosphorus, and
`dotions of this crucial intracellular element must be made
`10 Solutions of this nitrogen source.
`The amino acids in the i.v. c rystalline amino acid prod•
`ucts currently commercially available In this country are
`present as the acetate and chloride or hydrochloride salts.
`These preparations are acidic and the addition of inordinate
`amounts of sodium and/or potassium chloride can result In
`hyperchloremic metabolic acidosis in some patients, partlc•
`ularly those in pediatric and geriatric age groups. There(cid:173)
`fore, sodium and PQtasslum should be added to the base
`solution as the acetate. bicarbonate, chloride, lactate, or
`acid phosphate salt a.s dictated by the patient's acid-base
`status and serum electrolyte concentrations. Despite the
`fact that phosphorus has been added to some of the more
`recent commercially available amino acid solutions in mod•
`erate amounts, our experience indicates that an additional
`15 to 20 mEq of phosphate . as the potassium acid phos•
`phate salt, must be added to each liter of solution to main•
`lain normal serum phosphate concentrations. especlaliy
`during the 1st week of therapy.
`Hypomagnesemia will often occur within to days of initl•
`ating IVH if sufficient quantities of magnesium have not
`been added to the solutions. Similarly. hypocalcemia wlll
`result ii adequate quantities of calcium are not provided,
`usually in dosages of 4 to 9 mEq calcium gluconate per day.
`Both the fat• and water-soluble vitamins must be added to 1
`liter ol lVH solution per day, and folic acid, vitamin K, and
`vitamin B,. are usually administered i.m . or l.v. once a week.
`In patients with bone marrow depression following chemo•
`therapy or radiotherapy. addition of these vitamins to the
`IVH solutions is preferable to l.m. injection In order to avoid
`hematoma formation secondary to impaired coagulation
`mechanisms. Serum albumin concentrations below 3 g/100
`ml should be corrected to levels of at least 3.5 g/100 ml by
`the dally administration ol 12.5 to 50 g of salt-poor human
`albumin , which can be added d irectly to the bottles or bags
`of IVH solution. Colloid osmotic pressure thereby can be
`restored promptli, and protein nutrition will be supple•
`mented. In most patients, albumin synthesis In the liver will
`be restored to no1mal within 7 to 10 days of IVH administra•
`lion, and exogen,us serum albumin will no longer be re(cid:173)
`quired. The formulation ol representative IVH solutions for
`infusion Into adult patient s with normal concentrations of
`serum electrolyte;, magnesium, phosphorus, and calcium
`is given In Table 1. The formulation of IVH solutions for use
`in infants Is outlined in Table 2.
`The minimum daily energy requirement necessary to
`maintain an adult patient In the basal metabolic state Is
`approximately 1500 cal/day. In the absence of adequate
`exogenous calories, energy Is generated primarily by lipoly(cid:173)
`sis and the conversion of tissue protein Into glucose via
`gluconeogenesis. The work of Cuthbertson (5) on the cata•
`bolic response following trauma in humans demonstrated
`that infusion of 150 g of dextrose per day can result In a
`significant nitrogen-sparing effect. These data have been
`subsequently confirmed by many groups and extended to
`
`2441
`
`Miltenyi Ex. 1026 Page 5
`
`

`

`S. J. Dudrick et al.
`
`Table 1
`Composition ol standard IVH solutions for adults
`Single unit method
`
`---
`
`Bulk method: 165 g anhydrous dextrose U.S.P.
`+ 860 ml 5% fibrin hydrolysate in 5% dex·
`trose.
`Sterilization through 0 .22-µ. membrane fil.
`ter under la~mlnar-flow, filtered-air hood
`Volume
`1,000
`Calories
`1,000
`Dextrose
`208
`Hydrolysates
`43
`Amino aeids
`Nitrogen
`Sodium
`Potassium
`Phosphate
`
`6 .0 (g)
`8
`(mEq)
`14
`(mEq)
`
`(ml)
`(Kcal)
`(g)
`(g)
`
`Stock solution method: 350 ml
`50% dextrose + 750 ml 5%
`protein hydrolysate In 5%
`dextrose
`Aseptic mixing technique un(cid:173)
`der laminar-flow, filtered·
`air hood
`1,100
`1,000
`212
`37
`
`5 .25
`7
`13
`
`Kit methOd: 500 ml 8.5% Fream(cid:173)
`lne II + 500 ml 50% dex(cid:173)
`trose
`Aseptic mixing with transfer
`apparatus
`1000
`1006
`250
`
`42.5
`6.25
`5
`
`10
`
`Additions to each unit of base solution (av. adult):
`Sodium (acetate, lactate, chloride, and/or bicarbonate), 40-50 mEq
`Potassium (acetate, lactate, chloride, acid phosphate), 20-40 mEq
`Magnesium (sulfate), 10-15 mEq
`Phosphate (potassium acid salt), 15-20 mEq
`Additions to only 1 unit daily:
`Vitamin A, 5000-10,000 U.S.P. units
`Vitamin D, 500- 1,000 U.S.P. units
`Vitamin E, 2.5-5.0 IU
`Vitamin C, 250-500 mg
`Thiamine, 25-50 mg
`Riboflavin, S-10 mg
`Pyridoxine, 7.5-15 mg
`Niacin, 50-100 mg
`Pantolhenic acid, 12.5-25 mg
`Calcium (gluconate). 4 .8-9.6 mEQ
`Optional additions to daily ration:•
`Vitamin K, S-10 mg
`}
`Vitamin B11, 10-30 units
`Follc acid, O.S-1 .5 mg
`Iron, 2.0-3.0 mg
`• Micronutrients such as cobalt, copper. iodine, manganese, and z inc are present as contaminants in hydrolysate
`solutions but may be given in plasma transfusion t10 ml/kg) once or twice weekly If desired.
`
`Alternatively may be given i.m. in appropriate daily or weekly dosages
`
`Table 2
`Composition of pediatric IVH solutions
`Final pH of 5.2 to 5.5 may be adjusted to neutrality immediately prior to infusion with sodium bicarbonate or sodium hydroxide.
`Additional sodium, chloride, or other electrolytes are added as indicated by metabolic studies. Trace element solutions must be specially
`formulated from zinc sulfate, manganese chloride, pota'9ium iodide, copper sulfate, or molybdenum chloride compounds or may be
`given as contained In plasma transfusion, 10 ml/kg twice weekly. Infusion of final solution given at rate o f 145 ml/kg/day to deliver 130eaV
`kg/day.
`
`Bulk method
`Dexlrose 5% in protein hydrotysate 5%
`Anhydrous dextrose U.S.P. (20% solution)
`Calcium gluconate 10%
`Multlple Vitamin Infusion
`Potassium phosphate monobaslc (2 mEq/ml)
`Magnesium sulfate 50% (4 mEq/ml)
`Phylonadione (10 mg/ml)
`Cyanocobatamin (100 units/ml)
`Folic acid (15 mg/ml)
`lmferon (50 mg elemental iron/ml)
`Trace elements (optional)
`
`Total volume per lot
`
`ml
`12,000
`2:200
`150
`100
`30
`5
`2
`2
`2
`1
`7
`
`- 14,500
`
`(2
`
`Single unit method
`Dextrose 5% In protein hydroly•
`sate 5% (20 g dextrose, 20 g
`hydrolysate)
`Dextrose 50%
`Sodium chloride (2 mEq/ml)
`Potassium acid phosphate
`mEq/ml)
`Calcium gluconate 10% (0.45
`mEq/ml)
`Magnesium sulfate 50% (4 mEq/
`ml)
`Multiple V itamin Infusion
`}
`~~ga1amin (vitamin 8 11)
`~~~0
`8
`Phylonadlone (vitamin K)
`hnferon (iron)
`Total volume per unit
`
`ml
`
`400
`
`250
`10
`13
`
`44
`
`2.4
`4
`
`Added to solution dailY
`or w eekly or given ,.m.
`intermittently
`
`- 750
`
`2442
`
`CANCER RESEARCH VOL,
`
`37
`
`Miltenyi Ex. 1026 Page 6
`
`

`

`Parenteral Nutrition
`
`relative magnesium deficiency. The body stores energy
`within the high-energy phosphate bonds of ATP. Although
`phosphate is found in high concentrations within bone, it
`apparently is not sufficiently labile or available for redistri(cid:173)
`bution rapidly throughout the body because hypophospha•
`temia will result regularly if adequate quantities of phospho(cid:173)
`rus are not administered simultaneously with the other nu(cid:173)
`trients in IVH solutions. As dextrose and amino acids are
`infused in sufficient quantities to promote tissue synthesis,
`high-energy phosphate bonds probably are replenished by
`the utilization of extraosseous as well as osseous phospho(cid:173)
`rus. If exogenous phosphorus is not given during IVH ther(cid:173)
`apy, severe symptomatic hypophosphatemia may result.
`As anabolism is promoted by IVH administration, an in(cid:173)
`creased daily intake of calcium may become necessary. In
`general, the calcium requirement is greater in a hypophos(cid:173)
`phatemic patient than in one who has normal serum phos(cid:173)
`phate levels. However, because of the reciprocal relation(cid:173)
`ship between calcium and phosphorus, the serum calcium
`level may remain normal or rise slightly as hypophospha·
`temia is induced . However, as increasing doses of phos(cid:173)
`phate are added to correct the hypophosphatemia, rapid
`and significant hypocalcemla, with its attendant untoward
`reactions, will ensue unless adequate quantities of calcium
`are infused simultaneously with the phosphate.
`One ampul of a mixture of fat· and water-soluble vitamins
`suitable for parenteral administration is added to any single
`unit of the daily regimen. Because the vitamins present in
`each ampul of Multiple Vitamin Infusion are generally in the
`therapeutic dose range, it is neither necessary nor advisable
`to admini~ter more than 1 ampul/day to a Patient. Hypervi(cid:173)
`taminosis A and hypervitaminosis D can occur within a few
`days or weeks if more than 1 ampul of multiple vitamins are .
`given per day. Because there is no commercially available
`parenteral vitamin preparation that contains vitamin 8 1:!,
`vitamin ·K, or folic acid, each of these must be added in
`appropriate dosages in addition to the other required vita(cid:173)
`mins. Failure to administer folic acid has resulted in fulmi(cid:173)
`nating megaloblastic anemia in some patients within 2
`weeks after initiation of total parenteral nutrition .
`Iron can be added to the solution on a daily or weekly
`basis in appropriately calculated doses or can be given by
`deep i,,t,. injection. In patients with less than 10 g of hemo(cid:173)
`globin per 100 ml, it is advisable to restore the normal ABC
`mass by transfusion of packed erythrocytes or whole blood
`prior to IVH. In some patients it may be necessary to give
`occasional transfusions of packed erythrocytes during the
`course of prolonged total parenteral nutrition, particularly if
`they are simultaneously undergoing chemotherapy or ra(cid:173)
`diotherapy. Trace elements such as cobalt, copper, iodine,
`manganese, and zinc are present as contaminants in most
`parenteral solutions, particularly in protein hydrolysates,
`and are therefore not added routinely to the IVH infusate. In
`newborn infants and in severely debilitated adults, however,
`the trace elements may be infused intermittently as specially
`prepared additives or provided alternatively by the adminis(cid:173)
`tration of 10 ml of plasma or albumin per kg body weight
`per week. In the near future, a commercially available prep(cid:173)
`aration of trace elements suitable for use in the IVH regimen
`will simplify the administration of these essential micronu(cid:173)
`trients.
`
`shOW that infusions ?f greater quantities of dextrose will
`result In only minor increases in nitrogen sparing . More(cid:173)
`over. infusions of fat emulsions to provide additional calo(cid:173)
`ries will result primarily in fat deposition with little or no
`,urther protein sparing unless nitrogen in the form of amino
`acids or protein hydrolysates is administered in adequate
`quantities simult~neously (8) . When amino acids are in(cid:173)
`fused together with the concentrated dextrose solutions in
`;VH , glycogenolysis is minimized and lean tissue synthesis
`;saugmented. However, if the provision of potential calories
`in the form of dextrose g reatly exceeds energy expenditure
`in 8 9iven patient, excess quantities of g lycogen and fat can
`be deposited In the liver with the result that hepatomegaly,
`right upper quadrant tenderness or pain , and disordered
`hepatic function can ensue. Fo r the average patient, a ratio
`of tSO to 200 cal/g of administered n itrogen appears to be
`the optimal ratio. Of course, under conditions in which
`1 energy expenditure is increased, relatively high quantities
`of calories must be provided. Finally, protein synthesis de(cid:173)
`pends somewhat upon the activity of the patient, and physi(cid:173)
`cal exercise is essential for adequate regeneration of skele(cid:173)
`lal muscle. For this reason, it is recommended that patients
`receiving IVH engage in a daily p rogram of physical rehabili(cid:173)
`lation and graduated activity as early as their clinical condi•
`lions will allow.
`Nitrogen and potassium deficits often coexist during pe(cid:173)
`riods of catabolism, in part because the muscle mass con(cid:173)
`tains 75% of the body's total potassium stores. During glu•
`coneogenesis, when skeletal muscle is lost for conversion
`lo energy substrates, potassium is released to the extracel(cid:173)
`lular fluid compartment and i:. excreted in increased quanti(cid:173)
`ties by the kidneys. It has been shown that, if a mixture of
`protein hydrolysates and hypertonic dextrose is given to a
`pclassium-depleted animal without sufficient potassium re(cid:173)
`plenishment, growth and positive nitrogen balance will not
`occur optimally (3). In order to achieve positive nitrogen
`I balance and tissue synthesis, the intracellular requirements
`of potassium must be met without producing excessive
`I extracellular hypokalemia. Indeed, catastrophic myocardial
`j dysfunction and arrhythmias can accompany serum potas-
`~um concentrations below 2 mEq/liter. The degree of po(cid:173)
`l lassium depletion generally parallels the degree of protein-
`I calorie malnutrition, but the total body potassium is not
`I centration in emaciated patients. Not until adequate i.v.
`I nutritional therapy is begun with the stimulatio_n of_anabo·
`lisnn and its accompanying movement of potassium onto th_e
`j cells does hypokalemia and a realization of the true m?gni-
`lude of the total body deficit of potassium become manifest.
` Therefore, the severely malnourished patient may _requore
`an initial dose of as much as 60 to 100 mEq of potassium per
`11)0() cal in order to maintain potassium equilibrium. As
`
`reflected accurately or finitely by the serum potassium con(cid:173)
`
`11
`
`l anabolism progresses and stabilization occurs, protein
`turnover returns to normal and potassium requirements will
`I Phosphorus and magnesium depletion parallel potassium
`be reduced commensurately.
`.
`I hypethesized that the mechanism for their loss 1s s1m1lar to
`I that for potassium. Magnesium concentration is much
` higher in the intracellular than in the extracellular compart·
`
`and protein depletion in the catabolic patlen~. and It 1s
`
`rnent, and loss of body cell mass probably results on a
`
`1.
`
`JULY 1977
`
`2443
`
`Miltenyi Ex. 1026 Page 7
`
`

`

`s. J. Dudrick et al.
`
`Maintenance of sterility is of utmost importance in the
`preparation of i.v. nutrient solutions. Aseptic mixing of the
`various components and additives under a laminar-flow,
`filtered-air hood is essential for maximal safety. Final for(cid:173)
`mulation of the solution should be accomplished in the
`pharmacy immediately prior to infusion in order to minimize
`growth and reproduction of any microorgan isms that might
`inadvertently gain entry to the solution. After the solutions
`are prepared, they should be refrigerated and infused within
`24 hr. Periodically, aliquots of IVH solutions should be
`taken and cultured for aerobic and anaerobic bacteria and
`fungi in order to monitor quality control over the aseptic
`mixing of the solutions.
`
`Central Venous Catheterization
`
`Thrombophlebitis, cellulitis, and damage to the formed
`elements of the blood can result if the hypertonic IVH solu(cid:173)
`tions are infused through a peripheral vein . For safe and
`effective delivery of the nutrient solutions, accurate cathe(cid:173)
`terization of a large-diameter vein is essential. Our hyperali(cid:173)
`mentation team has used the superior vena cava almost
`exclusively for infusion of IVH solutions. Access to this
`vessel is obtained preferably by percutaneous catheteriza(cid:173)
`tion of the subclavian vein by the infraclavicular approach.
`Superior vena cava catheterization via an external or inter(cid:173)
`nal jugular vein is possible and at times acceptable, but the
`catheter exit site and its occlusive dressing interferes with
`maximum freedom of neck motion and is uncomfortable to
`most patients. Moreover, it is difficult to anchor the delivery
`tubing to the patient's neck or to the side of his face .
`Catneter dressings are easier to apply, more secure, and
`less inconvenient for the patient when they lie on the upper
`thorax.
`Successful percutaneous subclavian venipuncture is de•
`pendent primarily upon the physician's knowledge of the
`anatomy of the subclavian vein and its related structures,
`his technical skill, and adequate filling and dilation of the
`vein. The latter requirement can be fulfilled by restoring
`circulating blood volume with colloid and/or crystalloid
`fluid administered by peripheral vein and by positioning the
`patient supine in the Trendelenburg position prior to at(cid:173)
`tempting venipuncture. A rolled sheet is placed under the
`thoracic spine between the scapulae to facilitate hyperex(cid:173)
`tension of the shoulders. The head is turned away from the
`proposed site of catheter insertion. The skin is prepared by
`shaving the hair from the upper thorax, neck, and shoulder
`on the side of catheter insertion. Th