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Reducing Costs and Patient Morbidity in the Enterally Fed Intensive Care Unit Patient

Posted on: Thursday, 10 February 2005, 03:00 CST

ABSTRACT. Background: Critically ill patients are at high risk for nosocomial infections and resultant organ dysfunction and death. These patients typically have protracted intensive care unit (ICU) courses and consume increasingly limited resources. Enterai nutrition with specific immunemodulating components has been previously shown to improve outcomes in select populations of patients, but results have been mixed in critically ill patients. Impact 1.5 (Novartis Nutrition, Minneapolis, MN) is a commercially available enterai formula containing ingredients known to improve several parameters of immune function. We hypothesized that administration of Impact 1.5 tube feedings would reduce the incidence of nosocomial infection and ICU resources in critically ill patients admitted to the ICU for severe trauma, burns, or sepsis insults. Methods: The Impact 1.5 group (n = 17) was compared with a historical cohort of ICU patients (n = 21) of similar illness severity that received a standard high-energy enterai formula. The incidence of nosocomial infections and mortality, and the consumption of multiple ICU resources were examined. A cost analysis based on these results was then performed to determine the cost effectiveness of this proprietary immunonutrition enteral formula. Results: A pronounced reduction in nosocomial pneumonia (12% us 52%, p < .01) was identified, with consequent trends toward a reduction in duration of mechanical ventilation and ICU length of stay. Urinary tract infections that may have less influence on ICU resources were increased in the Impact 1.5 group. No difference in mortality was identified, despite the inclusion of patients with severe sepsis in the study group. According to the average number of ICU days required for each study cohort, the Impact 1.5 group led to a cost savings of at least $193,350.00. Conclusions: ICU patients with significant illness severity experienced a decrease in the incidence of an important nosocomial infection that is commonly associated with increased use of ICU resources and length of stay. This decrease in patient morbidity led to substantial cost savings despite the small size of our study trial. (Journal of Parenteral and Enteral Nutrition 29:S62-S69, 2005)

The systemic inflammatory response syndrome (SIRS) is associated with a variety of physiologic insults and severe infection.1 Patients that exhibit progressive signs of SIRS are frequently admitted to the intensive care unit (ICU) because of associated risks for multiple organ dysfunction.1 The gut-liver axis is now recognized as an important determinant of the severity of SIRS,2 and the gut lumen of severely ill patients often becomes a reservoir for the bacterial species that cause nosocomial infection.3,4 Therefore, efforts have been directed at preserving gut mucosa integrity, preventing intestinal stasis, and avoiding overgrowth of pathogenic bacteria within the gut lumen.3,4 Enterai feeding stimulates the growth of the gut mucosa and encourages the release of gut-derived hormones that influence motility.3-5 Enteral feeding has been shown to reduce mortality and morbidity compared with parenteral nutrition in a variety of clinical settings and is the preferred route of nutrition support for patients with functional gastrointestinal (GI) tracts.6-9 Despite the use of standard enterai formulas, however, patients in the ICU continue to experience nosocomial infections that affect outcome and determine the use of ICU resources.

During the hypermetabolic, catabolic state associated with SIRS, certain ammo acids and other substrates are thought to become conditionally essential. 10-12 The relative absence of these substrates can then impair the host's immune defenses and compromise the host's ability to maintain the integrity of the gut mucosa. Other specific nutrients have been found experimentally to diminish the inflammatory response or act as antioxidants to minimize tissue damage caused by the mediators of inflammation.10-12 Commercial enterai formulations that combine standard high-nitrogen tube feedings with these immunemodulating nutrients have been administered to patients in the ICU. These formulations have been referred to as immunonutrition (IMN).

As these commercial IMN formulas are considerably more expensive than standard high-nitrogen enteral formulas, the preparations have been highly scrutinized for their clinical effectiveness. Many clinical studies have demonstrated that the administration of IMN diminishes markers of inflammation (ie, C-reactive protein, interleukin [IL]-6),13,14 improves parameters of the immune response (ie, polymorphonuclear cell phagocytosis, delayed-type hypersensitivity, IL-2 plasma receptors),15-18 and promotes earlier conversion of acute phase reactants to constitutive visceral protein.13,14,19,20 Attention has been focused, however, on the ability of IMN to reduce wound complications, nosocomial infection, and hospital resources. Several clinical reviews and meta-analyses have now been published that clearly define benefits of IMN for reducing patient morbidity in a variety of ICU patient populations.21-27 These improved outcomes have significant implications for ICU resource use and costs. Nevertheless, there have been very few reports on the cost effectiveness of IMN formulas.28-31

We present our experience with the use of the IMN formula Impact 1.5 (Novartis Nutrition, Minneapolis, MN) in a small study of patients having significant risks for septic morbidity that were admitted to the ICU of a community hospital. Clinical outcomes that influenced patient morbidity and ICU resources will be reported, and the effect of these findings on ICU costs will be examined.

MATERIALS AND METHODS

In an effort to improve patient care quality and reduce ICU resources, we sought to reduce the incidence of nosocomial infection in our critical care units. In addition to enforcing existing infection control practices, ensuring timely surgical debridement and drainage for source control, and using appropriate antibiotics, the opportunity to modulate the patient's immune defenses and maintain gut integrity through specialized enterai formulas seemed reasonable.

Given the favorable consensus recommendations from the U.S. Summit on Immune-Enhancing Enteral Therapy,32 we established a new clinical policy in 2001 defining the indications for using a commercial IMN enteral formula (Impact 1.5) in severely ill patients under the care of the trauma and surgical critical care clinical service (Table I). As existing literature suggested that a minimum amount of IMN may be necessary to achieve favorable results, only patients expected to receive a minimum of 5 days of feedings would be started on the specialized enteral formula. Criteria for discontinuation of the IMN are outlined (Table II), but because of budget constraints, the policy also dictated that the Impact 1.5 formula would be maintained for a maximum of 14 days. To determine if this nutrition intervention was cost effective and warranted future budget outlays, the Value Analysis Committee at our institution had requested a cost analysis for the use of this specialized formula.

TABLE I

Eligibility for Impact 1.5

TABLE II

Termination of immunonutrition

The Impact 1.5 patients were identified prospectively but were recruited in a serial consecutive manner according to the existing ICU IMN clinical policy. For comparison, a historical cohort was identified from our trauma registry by screening this registry over the preceding 5 months according to the eligibility criteria outlined in the IMN policy. The majority of patients in the study had a feeding tube placed beyond the pylorus. The caloric goals established for each patient were based on existing targets of 25- 35 kcal/kg per day according to each patient's estimated physiologic stress level. The tube feedings were advanced in 20 mL/h increments every 6 hours, as tolerated, to the prescribed goal rate. A complete day of enteral feeding was defined as a 24-hour period in which the patient received at least 50% of the tube feeding prescribed. Interruptions in the tube feedings were caused by invasive procedures or evidence of poor tolerance, such as gastric residuals exceeding 200 mL over 4 hours or significant abdominal distention. The ICU nursing staff was not blinded to the selection of the enterai formula and followed standard nursing protocols for delivery of the tube feedings. Collection of data was performed by chart review for both the historical cohort and the Impact 1.5 group.

Statistical Analysis

All analyses were performed using SPSS (SPSS, Inc., Chicago, IL) for Microsoft Windows (Microsoft Corp., Redmond, WA). Categorical data were analyzed by group using the χ^sup 2^ test. Interval data were analyzed by group by applying an independent t test. The Levene's test for equality of variances was used to determine if there were equal variances of the means. Statistical significance was defined as p < .05 using a 2-tailed test of significance.

RESULTS

From January to November 2001, we had identified 20 patients that satisfied the eligibility criteria outlined in our ICU IMN clinical policy (Table I). Of these patients, 17 had received at least 50% of their prescribed daily tube-feedi\ng goal for at least 5 days. According to reported evidence that a minimal threshold of IMN may be necessary to observe clinical benefit, we decided α priori to evaluate only those patients that received sufficient quantities of the Impact 1.5 formula. This latter population of 17 patients would be evaluated for the incidence of nosocomial infection and consumption of ICU resources and then compared as a group to a historical cohort of 21 patients that met identical criteria over the preceding 5 months (August to December 2000). The majority of patients evaluated in this study had sustained trauma, especially blunt trauma. In fact, the demographics of these 2 patient populations (Table III) are fairly similar according to comparisons of their age, Glasgow Coma Score (GCS), and Injury Severity Score (ISS). The Impact 1.5 group did include more female patients and burn injury victims and also included 2 patients with severe sepsis.

The protocols governing the initiation and progression of enterai tube feedings did not change over the interval of time extending from the historical cohort group to the completion of prospectively enrolled patients in the Impact 1.5 group. The nutritional goals were based on targets of 25 to 35 kcal/kg/d and a protein intake of 1.5 to 2.0 g/kg/d. As seen in Table IV, both groups, on average, received comparable amounts of kilocalories and grams of protein. The historical cohort group received, with only 1 exception, the commercial high-energy tube-feeding formula named Promote (Ross Laboratories, Columbus, OH). One patient received Jevity Plus, another formula produced by Ross Laboratories that contains fiber and provides 1.06 kcal/mL, 44.3 g/L of protein, and 34.7 g/L of fat. Only the Impact 1.5 contains L-arginine, fish oils, and nucleotides.

Comparison of nosocomial infections between the 2 groups reveals that the Impact 1.5 group had a statistically significant decrease in the incidence of nosocomial pneumonia (Table V). This difference represents an approximate 4-fold improvement in the occurrence of this troubling ICU infection. In contrast, the patient group that received Impact 1.5 experienced a 2-fold increase in the incidence of urinary tract infection involving the bladder. Most of these patients had longterm indwelling bladder catheters necessitated by the need for accurate intake and output fluid measurements. Of greatest concern was the fairly uniform high incidence of bacteremia experienced by these ICU patients despite the strict enforcement of sterile technique and infection control measures. These patients almost uniformly had central venous access, which is presumed to be the source for the majority of these blood-borne infections according to data from the National Nosocomial Infection Surveillance Studies conducted by the Centers for Disease Control and Prevention.33 Although these data warrant careful review of our existing protocols for central venous catheter insertion and routine catheter cares, they do suggest that even an immune-modulating enteral formula cannot compensate for a large infectious burden in the ICU patient.

TABLE III

Study group and historical cohort demographics

Even with the inclusion of patients with severe sepsis, there was no increase in the incidence of mortality in the Impact 1.5 group. Although a high incidence of mortality may have been anticipated with our significant rate of bacteremia, the mortality of each group was ≤10%.

Mechanical ventilator support accounts for a large proportion of the cost of ICU care and represents a limited ICU resource. Efforts to reduce the duration of ventilator support often result in decreased lengths of stay in the critical care unit. We found that the Impact 1.5 group required an average of 3 fewer days of mechanical ventilator support and had an average length of stay in the ICU of 33 days compared with 38 days for the group that received the previous standard enterai formula. Although these differences did not achieve statistical significance because of large standard deviations and the small size of the study groups, they constitute important clinical trends with large potential financial savings. Despite 12% of the Impact 1.5 group having a diagnosis of severe sepsis at the outset, the average number of antibiotic days were nearly identical for the 2 groups. Consistent with the shorter overall stay in the ICU, the Impact 1.5 group received fewer days of enterai nutritional support, and this result was statistically significant.

TABLE IV

Study group and historical cohort nutritional data

DISCUSSION

It is now well recognized that injury, in addition to several other insults, results in a neuroendocrine response with the release of counterregulatory hormones35,36 and an inflammatory response that is characterized by the predominant type of mediators encountered.37,38 This stress response can therefore assume a proinflammatory tendency with early clinical progression to multiple organ dysfunction syndrome (MODS) or be dominated by an antiinflammatory milieu with resultant anergy and immunosuppression.38-40 Furthermore, it appears that the magnitude of the stress response and its consequences are influenced by several factors, including genetic predisposition, protein-calorie nutritional status, recent immunologie events, and the intensity, repetitiveness, and duration of the inciting insult.41-43 The patient clinically experiences hypermetabolism and catabolism associated with overall diminished immune defenses.40,44-46 Such patients cared for in the ICU consequently endure nosocomial infection that can lead to a late form of MODS.3,38,39 The gut- liver axis appears to have a significant role in influencing both the vulnerability of the host to such infection and the severity of its consequences.2,3 The integrity of the gut barrier relies on the ability to maintain the intestinal and colonie mucosa, preservation of the normal gut flora, and maintenance of peristalsis.3,4 Lack of GI feeding has been shown to cause atrophy of the mucosa, loss of bile salts and secretory immunoglobin A (IgA), which are important for preventing the binding of pathogenic bacteria to the mucosal lining, and diminished gut hormones that results in the loss of peristaltic activity.3,4 In the presence of intestinal stasis, the use of potent, broad-spectrum antibiotics seems to promote the overgrowth of pathogenic bacteria.47,48 An increase in gut permeability has been blamed for bacterial translocation in which bacteria trapped by the gutassociated lymphatic tissue leads to the portal or lymphatic distribution of endotoxin or inflammatory mediators.3,4 In animal models, bacterial translocation has resulted in transfer of the bacterium itself into the portal venous system.49 After bacterial translocation, the Kupffer cells of the liver are activated and, in addition to the systemic liberation of tumor necrosis factor-α, IL-1, and IL-6, signals are processed to result in a shift of protein synthesis within the liver from constitutive visceral proteins to acute phase reactants.2 This up- regulation of inflammation can exacerbate an existing SIRS associated with the original insult that led to admission to the ICU.1,38,39 The host immune response that relies on a finely coordinated adaptive immune system becomes seriously impaired. With the overgrowth of pathogenic bacteria, the upper GI tract can become colonized if the patient receives agents to reduce gastric acid secretion.50 Given the risk of aspiration and violation of multiple natural barriers of infection (eg, invasive catheters, endotracheal tube), the patient is especially susceptible to nosocomial infection.51,52

TABLE V

Study group and historical cohort clinical outcomes

The majority of the literature addressing nutrition in the ICU, especially enterai nutrition, has reported on the outcomes experienced by surgical patients.8 If sufficient calories are not provided to the patient in the hypermetabolic, catabolic state, the acute protein-calorie malnutrition causes excessive skeletal muscle proteolysis to occur, followed by depletion of crucial visceral and circulating proteins.53 The use of enterai nutrition has been shown to better maintain the integrity of the gut mucosa and to improve several nutrition markers compared with total parenteral nutrition.7- 9 These benefits have been achieved even though enteral feedings tend to deliver fewer overall calories.9 Because of the composition of enterai feedings, they are associated with less risk for hyperglycemia.9 Although the definition of early enteral nutrition varies across published papers, in general, delayed enterai nutrition is initiated > 72 hours after admission. Heyland54 found during a review of the relevant literature that the early introduction of enteral feedings in adult surgical patients is associated with a reduction in infectious complications and possibly a shorter hospital stay. He acknowledged that early enteral nutrition warrants a grade B recommendation in critically ill surgical patients and, because of a lack of data, suggested a grade C recommendation for other critically ill patient populations. The reduction in infectious complications has been attributed to the typical use of high-nitrogen formulas.45,55

Despite the benefits of enteral nutrition, patients in the ICU that have sustained a significant physiologic insult continue to develop nosocomial infections as a result of their associated immune dysfunction. To respond to this challenge, special formulas have been devised that combine the contents of standard highnitrogen enteral formulas with nutritional components that have been shown experimentally to enhance parameters of immune function or subdue inflammation. These enhanced formulas have been collectively termed IMN, but the commercial formulas do differ somewhat in their contents.

Numerous reports on the use of IMN have been p\ublished, and collectively these reports suggest a potential biologic explanation for the mixed results observed in critically ill patients. As a whole, these studies indicate that the patient must receive a sufficient quantity of the IMN formula and that improvements in immune function will not occur until these components have been sufficiently assimilated, typically at least 5 to 7 days after initiating the IMN feedings.14,16,19,23,25,56-59 In fact, the studies found that infections may only be reduced in a delayed fashion or continue to occur but with less severity.13,29,60,61 Allowance for such delivery thresholds and delays in effectiveness has created problems for investigators attempting to interpret the results of properly conducted trials on an intent-to-treat basis and has made it necessary to examine subgroups for successful outcomes. These facts, combined with the use of heterogeneous ICU populations, probably account for the inconsistent statements that have been rendered about the benefits of IMN. In addition to the U.S. Summit on Immune-Enhancing Enterai Therapy in May 2000,62 there have been several review papers,23,25,26 and meta-analyses21,22,24,27 performed on these clinical trials that essentially focus on 3 main patient categories: elective surgical patients undergoing procedures for GI tract cancer, patients that sustained injuries (ie, burns or multisystem trauma), and a mixed group of critically ill patients that includes a large percentage of patients with pneumonia as a cause for their sepsis. None of these critical reviews have found statistical evidence that IMN is associated with increased mortality within any of these patient populations. In fact, despite the controversy about L-arginine within these formulas, 63-65 Heyland et al24 found significantly less infection and no increase in mortality among those studies that used an IMN formula containing a high content of L-arginine. Although a decreased number of infections and a decreased length of hospital stay has been consistently demonstrated in each meta-analysis, we are reminded by Montejo et al27 that patient populations exposed to different insults experience slight variations in the benefits obtained with IMN. These outcome differences between patient populations and the inconsistent results between individual studies most likely reflect the effects of risk stratification. As pointed out by Atkinson et al,58 McCowan and Bistrian,25 and again by Galbn et al,66 the patients most likely to benefit from IMN are those that are at intermediate risk for nosocomial infection according to their severity of illness.

In the data presented from our experience with Impact 1.5, it is evident that not all nosocomial infections among a study cohort will be reduced. If the bacterial burden is excessive, modulation of the immune response will not prevent tissue invasion and clinical infection from occurring. Our data demonstrate that bacteremia and urinary tract infection (UTI) were highly prevalent among the patients in our ICU at the time of this study. According to known risk factors for these infections,33,67 we suspect that more rigorous infection control measures need to be implemented to reduce the bacterial burden associated with the central venous and arterial catheters and with the indwelling bladder catheters on our critical care units.68 With regard to the higher incidence of UTI among the Impact 1.5 group, it is plausible that the difference observed was contributed, in large part, by the higher percentage of female patients. The short urethra of the female and the protracted use of an indwelling bladder catheter are well-known specific risk factors for UTI.67 The resultant excessive bacterial burden could readily overcome any improvement in the immune response contributed by the Impact 1.5 formula. In these situations where the bacterial burden overwhelms the host defenses, the principal influence of the IMN would be to ameliorate the systemic inflammatory response. The reduction of ICU days and the earlier liberation of patients from mechanical ventilation within the Impact 1.5 group reflect the fact that SIRS was not worsened among these patients despite the higher incidence of UTI. Although UTI can be effectively treated with short courses of antimicrobials, the treatment of bacteremia often requires a more prolonged course of systemic antibiotics. Therefore, the high incidence of bacteremia in both patient groups accounts for the similar use pattern of antibiotics.

In comparison to the IMN trial of Atkinson et al,58 in which the patients received total calories well below their prescribed amounts, we delivered, on average, significantly more daily calories with both enterai formulas. This success can be attributed to our policy of using nasojejunal feeding tubes that are placed by the critical care nurses and monitored radiographically with the purpose of achieving enterai access beyond the pylorus. Metoclopramide was administered to aid with proper placement if the tip of the catheter remained in the antrum of the stomach. If these measures were not successful, patients were sent to radiology for placement of the feeding tube under fluoroscopic guidance. To avoid delays in enterai nutrition, patients were fed in the stomach short term until proper placement of the feeding tube was achieved. The dedicated effort to achieve cannulation of the small bowel was motivated principally by concerns for safety to prevent aspiration.69 Both tube-feeding formulas were well tolerated. As emphasized by McCowen and Bistrian,70 the achievement of early enterai access is more likely to expedite sufficient IMN uptake to achieve the immunologie benefits.

Perhaps our use of nasojejunal enterai access and early enteral feeding, along with nursing routines that provided adequate oral cares, decreased the bacterial burden to the respiratory tree. Under such circumstances, differences in the host immune defenses would have a more pivotal role in determining the onset of nosocomial pneumonia. Although the patients in each group, on average, had rather prolonged courses of mechanical ventilation, we were able to achieve a significant reduction in the incidence of nosocomial pneumonia in the Impact 1.5 group (12% vs 52%, p = .01). Patients with nosocomial pneumonia often need additional days of mechanical ventilation until clearance of the infection permits sufficient improvement in the alveolar-arterial gradient to safely permit liberation from the ventilator. This reduction in nosocomial pneumonia probably accounts, in large part, for the findings of fewer days of mechanical ventilation and decreased length of stay in the ICU in the Impact 1.5 group.

The motivation for performing our study was to address the issue of cost effectiveness as the Value Analysis Committee at our institution mandated that a formal evaluation be completed before approving Impact 1.5 for the nutrition formulary. Because the use of Impact 1.5 was determined by the eligibility criteria of our new clinical IMN ICU policy, there was no effort to perform randomization, and we relied on a historical cohort group for comparison. In addition, because the analysis was intended to determine cost advantages, it seemed most reasonable to evaluate only those patients that received sufficient amounts of the Impact 1.5 according to previous published reports. Thus, we had established a priori that we would evaluate only patients in each group that received at least 50% of their daily enterai feeding goal over at least 5 days. Statistical evaluation of most of the examined outcomes was hampered by the small number of patients and by large standard deviations that were encountered because of the heterogeneity within each feeding cohort. Other than ensuring that the patients were sufficiently ill to warrant the use of IMN, we made no additional attempt to exclude specific diagnoses known to consume greater ICU resources and to have prolonged stays in the ICU. At the time of this study design, we were greatly influenced by the perspective of Barton,71 who recommended that the more expensive IMN formula should be reserved for the most severely ill patients at risk for septic morbidity. Consequently, we included within both groups patients having profound head injuries and victims of spinal cord trauma associated with quadriplegia. These patients are highly susceptible to nosocomial infection, but they commonly experience prolonged mechanical ventilator dependency because of their cerebral and neuromuscular impairment and not solely because of respiratory failure attributed to metabolic or infectious maladies. Only the latter causes would be expected to respond favorably to a therapy intended to modulate the immune response. Although the decrease in the number of mechanical ventilator days and the duration of stay in the ICU did not achieve statistical significance, the difference in the mean values of these ICU resources did result in real cost savings for our institution. Despite a nominal increase in the nutrition budget of $10,650.00 for Impact 1.5, the recovered savings in ICU costs (based on 5 fewer ICU days at $2400.00/ICU day34) was $193,350.00 (less costs for treating 4 additional UTIs). This cost savings was achieved with only 17 patients.

The report of our data has several inherent limitations that prevent any broad conclusions about the use of IMN in the ICU population. But the strength of the data is that it reflects important points about clinical expectations and risk stratification. IMN can only demonstrate its purported benefit of enhanced immune defenses if the bacterial burden is simultaneously managed with proper infection control practices. This study also reemphasizes the difficulty of study interpretation when confounding factors are introduced that can influence outcome variables. The cerebral and neuromuscular impairment of p\atients with very severe closed head injury and spinal cord trauma will prolong mechanical ventilation and length of stay in the ICU. When such patients are included as part of a relatively small and heterogeneous group of patients, they will alter the power of the study if such outcomes are the primary endpoints of the investigation. Despite all of these limitations, we were able to achieve a reduction in an important source of infectious morbidity and, consequently, decrease the use of ICU resources. Given fixed diagnostic-related group reimbursements for hospitalization and limited ICU bed availability, the reduction in ICU stay with IMN has tremendous financial and ICU resource implications.

ACKNOWLEDGMENTS

The authors thank Jenny LaChance, MS, CCRC, and Julie Campe, CCRC, for their assistance with the statistical analysis. We also want to express our appreciation to the dedicated nurses of our Neuro Trauma ICU and Burn Unit for their excellent patient care.

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Mitchell S. Farber, MD, FACS*; Julia Moses, MS, RD[dagger]; and Margaret Korn, RD, CNSD[dagger]

From the * Department of Trauma and Surgical Critical Care and the [dagger] Department of Nutrition Services, Hurley Medical Center, Michigan State University College of Human Medicine, Flint, Michigan

Received for publication August 2, 2004.

Accepted for publication August 30, 2004.

Correspondence: Mitchell Farber, MD, Neuro Trauma ICU, One Hurley Plaza, 7 West Trauma Services, Flint, MI 48503-5993. Electronic mail may be sent to mfarberl@hurleymc.com.

Copyright American Society for Parenteral and Enteral Nutrition Jan/ Feb 2005

Source: JPEN, Journal of Parenteral and Enteral Nutrition

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