Energy replacement during parenteral nutrition in surgery, sepsis and cancer

CLINICAL NUTRITION (1984) 3:' 125-131 EDITORIAL

REVIEW

Energy replacement during parenteral nutrition in surgery, sepsis and cancer j. Faintuch* R. Krause and R. L C. Wesdorp Department of Surgery, University of Limburg, Maastricht, The Netherlands *Present address: Department of Surgery, Hospital Das Clinicas, Sao Paulo, Brasil, (Reprint requests to RICW)

For many years, the increased nutritional requirements o f surgical, septic and cancer patients were identified, but no effective therapy existed for averting their negative calorie and nitrogen balance. Parenteral nutrition offered an answer in many o f these situations. However, abnormalities in liver function, ventilatory load, hyperglycemia and a disturbed metabolic homeostasis showed that in excessive amounts, glucose can behave as a relatively toxic substance. For cases with increased energy expenditure, new alternatives had to be devised in order to avoid excessive glucose intakes. One obvious possibility in these cases was to refrain from offering more than the basal caloric needs, until the patient had passed the period o f acute injury, or other measures had effectively'controlled the sepsis or cancer. Other options included the partial substitution o f glucose by lipids or amino acids. Preliminary information suggests that this approach could lead to better nutritional outcome and survival rates, but additional studies are required.

ABSTRACT

INTRODUCTION

HISTORICAL CONSIDERATIONS

During recent years, there has been increasing recognition of the potential hazards of hyperalimentation or highcalorie parenteral nutrition, when applied to seriously ill patients. Not only the hepatic physiology [1-3], but also the respiratory dynamics [4,5] and general glycaemic and electrolyte homeostasis [6] can be affected by hyperalimentation. These findings impose restrictions on the fulfillment of the increased caloric requirements often found in hypermetabolic subjects suffering from 'autocannibalism' [7]. Although the advent of computerized devices for day-to-day determination of total energy expenditure holds the promise of an exact knowledge of each individual's needs, some methodological shortcomings remain [8,9]. Additionally, it may well be the case that there is a fixed limit for liver oxidation of infused glucose, which does not accompany augmented demands eventually induced by complications [I0]. Furthermore, it is not clear whether a richer, physiologically adapated substrate will reduce mortality in critical conditions, although available data tend to be in agreement with this hypothesis [7,11,12]. In this paper the problems accompanying massive glucose infusions will be outlined, within the context.of the energy demands of surgical, septic and cancer patients. Some disputed aspects of the actual needs ofsuch seriously ill cases will also be summarized, as well as the possibility of meeting abnormally elevated requirements with modified, potentially safer substrates.

Wilmore et aL [t3] emphasized that during many centuries, the accepted regimen for febrile states was total fasting, with prohibition of even water intake. Early 19th century workers advocated some alimentation, but it was only with the studies of Coleman and Dubois [14], in 1915 and particularly after the carefu'l compilations by Harris and Benedict [15], that the real caloric or energy expenditure of the patients started to be appraised. Soon after the introduction of parenteral nutrition a consensus was created around the 3000-4000 kcal/day energy provision especially for very sick surgical patients. However, such levels of intake can by themselves pose problems for elderly, emaciated patients, or for cases in developing countries, where the typical body weight can be considerably lower than the traditional 70 kg model [16]. Notwithstanding these limitations, such regimen was soon adopted in many parts of the world [I 6,17] and usually led to therapeutic successes. The fundamental statements of Cutherbertson [18,19] that severely traumatized patients respond poorly to oral alimentation were subsequently reaffirmed for intravenous feeding. As a result, even more calories were administered as a means of achieving a positive nitrogen balance. Thus Aguirre et al. [20] gave 4500 kcal/day t.o some patients with enterai fistulas. Himal et al. [21] used up to 5000 kcal/day in 1974 as did Faintuch et al. [22] during the same time period. For burn patients, a total intake reaching 7000 t o I0 000 kcal was deemed appropriate in some circumstances [231.

125

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ENERGYREPLACEMENTDURINGPARENTERALNUTRITION IN SURGERY,SEPSISAND CANCER

It must be stressed that Canadian and European [25] investigators were often more cautious in not exceeding the administration of 40-50 kcal/kg/day. On the other hand, experimental studies were abte to demonstrate that high doses of glucose were damaging to the liver [26]. Chang and Silvis suggested in 1973 [27] that even in the presence of adequate amounts of amino acids, an exaggerated caloric input could produce fatty metamorphosis of the liver. Only reduction of the glucose load could reverse the hepatic infiltration.

ASSOCIATION WITH ENZYMATIC ABNORMALITIES OF T H E LIVER In a classical review of metabolic complications of intravenous hyperalimentation, Dudrick et al. [28] in 1972 pointed to three possible explanations for hepatic dysfunction: (a) enzymatic induction by nutritional substrates (b) excessive accumulation of glycogen or fat, and (e) true cholestasis dependent on reduced water content of the bile: Typical cholestasi~ does occur in some children, but inspissation of bile is seldom seen [29]. In the adult, where histologically demonstrable cholestasis is rare, a large list of potential causative agents have been incriminated in recent years such as inappropriate calorie/N ratio [3,30], continuous administration during 24 h [31], toxicity of amino acids [32], breakdown products of tryptophan [33], intolerance for lipids [25,34], essential fatty acid deficiency [35], vitamin deficiency [36], and biliary lithogenesis [37]. Foremost in the pathogenesis of enzymatic disturbances in the opinion of many groups [1,38-41] is the role ofsupranormat energy administration and utilization in the form of hypertonic glucose. A hL~man 'pat6 de foie gras' could therefore be predicted on the basis of deliberate prolonged overfeeding

[21. THE RISK OF R E S P I R A T O R Y C H A N G E S

Since 1980 a new side-effect of vigorous energy administration has been described, namely overproduction of CO s and eventual respiratory insufficiency, particularly in the presence of associated serious pulmonary disese [4,5]. The syndrome is mostly confined to malnourished and septic subjects, who are prone to receive caloric overloads and seem very susceptible. The original report refers to the administration of 2.25 times the basal energy expenditure of a patient (approximately 4400 kcal/day) when an increase of 67% in the production of CO s ensued and triggered respiratory distress, which was only relieved when the caloric input was reduced to low levels. In addition to CO2 accumulation, Askanazi et al. [4,5] and others were able to document a higher oxygen consumption, together, with

occasionally elevated excretion of endogeneous norepinephrine. This last abnormality, which is particularly seen in septic subjects, could indicate that a 'stress' reaction is probably activated in this situation. Up to 459o of the infused calories can be lost in a non-productive way in such patients because of the increased metabolic expenditure. At the same time, cardio-respiratory reserves have to be mobilized in order to meet the expanded O2 and CO2 exchange rates. Torosian et aL [42] have proposed a connection between the hepatic and pulmonary problems. In their experience with measurement of the respiratory-quotient (RQ) of candidates for parenteral nutrition, two patterns could be recognized. Some patients showed an increase of the RQ of at least 5% after a test dose of amino acids and glucose, whereas all the others showed only minor changes. Pulmonary complications never occurred in their cases but in regards to liver enzymatic abnormalities, the first group had an incidence of 77%, in contrast to the second group with an incidence of not more than 17%. Since important increases of the RQ are always associated with hepatic lipogenesis, which follows the administration of glucose loads in excess of the oxidative capacity ofthe liver, it is not unreasonable to link these two phenomena together with increased circulating enzymes on one side, and with CO: accumulation on the other side.

OTHER METABOLIC D E R A N G E M E N T S Altered phosphate metabolism is not usually seen in seriously sick patients with surgical conditions [43]. However, symptomatic hypophosphathemia was common many years ago, when supplementation with this mineral was not practised during parenteraI nutrition [44]. Massive infusions of'glucose and other carbohydrates can characteristically induce rapid shifts of phosphate from the extracellular to the intracellular compartment. Two fatal cases have been published recently by Weinsier and Krumdieck [6] having, in addition, hyperglycemia and refractory circulatory decompensation. These cases illustrate the difficulty of the regulatory mechanisms in coping with unphysiotogic caloric intakes in the range of 70 kcal/kg/day. PECULIARITIES O F NUTRITIONAL RESPONSE IN TRAUMA AND SEPSIS One of the most obvious censequences of trauma and sepsis is a negative energy and nitrogen balance. These phenomena have been investigated by many authors and the main participating mechanisms [7,19,45-47] are summarized and compared with uncomplicated starvation in Table t.

~LINICAL NUTRITION

Table I

127

Metabolic differences between uncomplicated starvation and sepsis and trauma [see refs. 19, 45-47]

Pathophysiology

Sepsis and trauma

Proteins

Marked increase in nitrogen excretion. Active gluconeogensis, accelaratlon of the glucose-alanine cycle. High utilization rates with even higher glucose output. Insulin resistance, tendency to hyperglycemia. Production and oxidation of fatty acids is increased, with no accumulation of ketones. Expenditure up to 100% above basal levels, in proportion with severity of iniury.

Carbohydrates

Lipids

Energy requirements Response to realimentation

Difficulty to achieve N-equilibrium. Supranormal demand//.of calories and I-rotein.

The protein sparing pMnornena that ~'e clearly operative during simple starvation, seen,, to be suppressed in conditions of acute 'stre.~s'. "]'la]~ ,.'~ergy-inefficient system is not amenable to si.~p]e ~h~rapeutic restoration and especially enriched nutritional regimens with modified Cal/N ratios may be required, in order ~o obtain nitrogen equilibrium [7,19,25,45,46),,

E N E R G Y R E Q U I R E M E N T S IN C A N C E R PATIENTS Malignant tumours can induce important changes in host nutritional status, affecting energy expenditure and the metabolism of carbohydrates, lipids and proteins. Weight loss is a common manifestation, sometimes to the point of overt cachexia. It has long been demonstrated that this cachexia can be more resistant to nutritional therapy than other forms of malnutrition, even under conditions of force-feeding [48]. After the introduction of parenteral nutrition, evidence about inappropriate nutritional response continued to accumulate. Occasional weight gain was obtained, but this was mostly due to fat synthesis and water retention, with no increase in lean body mass or survival rates [49-51]. Moreover it has been shown both clinically and experimentally that many forms of cancer, at least during certain phases of evolution can interfere with diverse mechanisms of nutritional physiology (Table 2). Protein metabolism is not preserved in the presence of c a n c e r and c h a n g e s i n v o l v i n g s e r u m a l b u m i n concentration, aminoacid metabolism, protein turnover and nitrogen balance have been recorded [62,63]. Lipid mobilization and uptake was also found to be abnormal, with a tendency towards fat wasting [61,64]. In regard to glucose metabolism, increased turnover and recycling as

Uncomplicated starvation Progessive economy of nitrogen, with reduced gluconeogenesis. Low urinary elimination of N.

Low glucose levels, with reduced liberation and consumption of carbohydrates. Bl'eakdown of fatty acids in the presence of low insulin induces typical ketosis. Gradual reduction in energy consumption as a consequence of adequate calorie sparing mechanisms. Increased avidity for N. Prompt and vigorous anabolism upon refeeding.

Table 2 Abnormalities of energy regulation in cancer Abnormality

Reference

Anorexia, reduced energy imake, altered central metabolism of tryptophan Increased energy expenditure Hyperglycemia, insulin resistance Excessive gluconeogenesis 'Futile' metabolic cycles, excess lactate turnover

[51, 52, 53] 154-56t [57-581 I57, 60, 61] [57, 58, 62]

well as inadequate oxidation are described [51,52], reflecting both turnout and host metabolic activites. In spite of normal or elevated glucose levels, gluconeogenesis is increased and a relative insulin resistance can be seen [57-59]. Cori-cycle activity and lactate release can be abnormally increased, sometimes as a direct consequence of glucose infusion, as observed by Goodgame et aL [65]. Nevertheless, not all cancer patients behave in a similar way, and conflicting views surrou~d the pathogenesis of cancer cachexia. Indeed, Bennegard et aL [66} were unable to detect any characteristic alteration in the uptake of glucose and release of alanine or glycerol, when they compared weight losing cancer patients with control cases. They rejected the possibility that cancer metabolism is unique and attributed all known modifications to an adaptive response in face of nutritional deprivation. In addition Lennard et aL [67] could not find any significant difference in body composition of cancer and non-cancer patients, as investigated by routine nutritional assessment. They conclude that ifcancer cachexia is a specific entity, it cannot be detected by clinical measurements. Certainly not all cancer patients are hypermetabolic [54] and some o f them benefit as'much from nutritional support as others with a simple energy deficit [49,52]. For those who have the metabolic abnormalities however, adequate nutritional therapy constitutes an important challenge.

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T H E PLANNING OF CALORIC REPLACEMENT FOR SERIOUSLY ILL PATIENTS In response to the metabolic abnormalities described above several recommendations tbr the prescription of parenteral nutrition in situations of surgery, sepsis and cancer have been formulated. One of the most traditional recommendations was to supply to febrile patients an excess of 8-13% of calories, for each degree of mean temperature elevation [23,68]. Other therapeutic proposals took into account the expected energy losses accompanying each disease c a t e g o r y [69]. T h u s e m p i r i c a l supplementations of up to 100% of the basal calculated expenditure were used, when the patient was faced with a major metabolic insult. With the recent availability of better methods for indirect calorimetry, new information was gathered about the actual requirement of each case and equations were derived for the rapid estimation of the patient's needs. Representative of this modern approach is the protocol suggested by Long et aL [70], where the basal rate given by the Harris-Benedict formula is corrected by an activity factor and an injury factor. The former can vary between t.2 and 1.3 and the latter between 1.2 and 2.1. It can therefore be concluded that the final increment, in certain circumstances, will still be in excess of 100% of the basal value. Since this is the range where metabolic dangers are likely to occur, the alternative for avoiding those sideeffects is to compromise with a smaller energy load, accepting as a consequence a smaller nutritional effect. This conservative management was strictly followed by Apelgren and Wilmore [711, who introduced more modest injury factors. The authors use an allowance of l.O00 kcal/day when weight gain is desired, but emphasize that for most critically ill patients protein maintenance and not a positive nitrogen balance should be the goal. The confirmation by Quebbeman and others [72] that the extra losses of critically ill subjects do not commonly exceed 25-30% of their basal requirements and sometimes stay well within the range of non-stressed ind;.viduals, further reinforce the former policy. In a recent analysis of 49 very sick surgical patients of whom 70°70 had sepsis, 30% had cancer and in addition there were other factors contributing to nutritional failure [73]. Dangerous hyperglycemia, hypercapnia, hypophosphatemia or lactic acidosis were not a problem in this group, but liver enzymatic abnormalities were a frequent finding. Minimum requirements for weight and albumin stabilization were, as expected, high with a mean value of 40 kcal/kg/day. Inputs above 51 kcal/kg/day were accompanied by an increased incidence of deranged alkaline phosphatase levels and those were seen not only in cases where the minimum needs had been exceeded, but also when the patients depended on exceptional intakes to attain nutritional equilibrium. Increased demands can therefore coexist with diminished

tolerance, a phenomenon that should be remembered when glucose prescriptions are calculated.

SPECIAL FORMULATIONS FOR T H E PREVENTION OF METABOLIC COMPLICATIONS In order to ensure an integral replenishment of energy losses during surgery, cancer and sepsis in the presence of elevated demands, it will probably prove advantageous to consider other caloric substrates in exchange for current dextrose-based preparations. A number of preliminary impressions is available, endorsing the safety of lipid emulsions [5,25,74]. They have been successfully utilized in many critically ill patients, including septic cases, although not everybody agrees on this latter indication [75]. Others prefer the amino acids themselves, in increased concentrations, as a source both of building blocks and ~f energetic material for the management of vital body needs. Again this approach cannot be considered as being ideal because protein-rich regimens have their own potential dangers [76]. Very encouraging results have been obtained with branched chain amino acid enriched formulations due to the unique properties of these compounds which provide the liver and muscles with a readily available substrate. Some workers dispute their efficacy in the clinical setting [77], but there are series which show convincing advantages for this type of therapy [45,78-80] and cancer patients seem to conserve: their muscle mass better when such therapy is used [81]. When we are dealing with malignant disease attention should be given to the potential implications of the adjuvant nutrition on tumour growth and longterm survival [82]. Even ifcancer proliferation is enhanced, new techniques of cyclic administration of anti-neoplastic agents can still maintain the opportunity for disease control and ultimate Favourable outcome [83].

CONCLUSIONS Surgical, septic and cancer patients present some of the most complex problems for nutritional management. With a negative energy and nitrogen balance, although dependent on different pathogenic phenomena, they share some important similarities [5t]. These include a tendency to elevated metabolic rates despite progressive weight loss [47,55], and excessive gluconeogenesis [45,46,58,59]. Metabolic mediators of muscle proteolysis in sepsis and trauma have been identified [84], but many uncertainties still cloud our understanding of tumor-host interaction during excessive gluconeogenesis and glucose turnover in cancer patients [57,58]. The possibility of pharmacological suppression of

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hypermetabolism and of nutritionaa control of abnormal gluconeogenesis, open fascinating prospectives for the future [52,63]. New caloric substrates might also replace current energy sources, enhancing the correction of energy deficit in the most difficult circumstances [78,81]. Until these promises become reality, there is a need for nutritional schedules that avoid excessive glucose intakes, because such prescriptions can have diverse and potentially troublesome side-effects. At present the most prudent

approach seems to be the provision of nutrients in physiological amounts. Strong anabolism is n o t a realistic goal in advanced cancer or severe injury and nitrogen equilibrium is not easily obtained i n these patients. By means of administration o f relatively modest amounts of caloric substrates, however, combined with appropriate proportions of nitrogen, nutritional stabilization can be achieved in many cases, and dangers of supranormal glucose prescriptions can be avoided.

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Submitted: 17 May 84. Accepted: 14 June 84.

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