Functional characteristics of the hypermetabolic isolated perfused liver.

Clinically, hypermetabolism of the liver accompanies the systemic response associated with trauma and sepsis. Although increased metabolism is generally considered a beneficial response, a markedly increased hepatic oxygen consumption (HVO2) may be associated with adverse consequences such as induction of centrilobular hypoxia. We studied the effects of lactate and glucagon as inducers of increased HVO2 in the isolated perfused rat liver to determine if hepatic functional derangements could be precipitated by these trauma-associated factors at high metabolic rates. HVO2 rose by 27%, 52%, and 70% in response to 5 mM lactate/1 mM pyruvate, 20 nM glucagon, or both, respectively. In response to these stimuli at a fixed perfusion rate, hepatic venous oxygen saturation declined to 48 +/- 4% at the highest HVO2, and this was associated with a reduced hepatic adenosine triphosphate content and fibrinogen secretion. These findings indicate that hepatic metabolic disturbances can result from hepatocellular hypoxia due to increased HVO2.

Systemic and splanchnic metabolic response to exogenous human growth hormone.

BACKGROUND: Evidence exists indicating that growth hormone (GH) resistance in some disease states such as hypercatabolic conditions may limit the metabolic benefit associated with recombinant human growth hormone (rhGH) administration. It was the purpose of this study to compare the systemic and splanchnic effects of rhGH in patients with sepsis exhibiting systemic inflammatory response syndrome (SIRS) with the response observed in normal volunteers. Because insulin-like growth factor I (IGF-I) is believed to be the dominant factor responsible for the anabolic effects of rhGH, particular attention was given to this secondary effector. METHODS: The systemic and splanchnic effects of rhGH (0.15 mg/kg/day) were studied in normal volunteers (n = 5), critically ill patients with sepsis exhibiting SIRS (n = 6), and patients with sepsis exhibiting SIRS while receiving total parenteral nutrition (n = 6). Basal and end study IGF-I, urinary urea excretion, hepatic blood flow, hepatic venous oxygen content, and splanchnic oxygen exchange were measured after a 48-hour course of rhGH. RESULTS: Fasting basal IGF-I concentrations were reduced by 75% to 83% in patients with sepsis/SIRS relative to normal control subjects. After 48 hours of rhGH, peak IGF-I concentrations were 74% and 76% lower in patients in the Sepsis/SIRS and Sepsis/SIRS + Nutrition groups, respectively, compared with normal control subjects. Despite the attenuated IGF-I rise in patients, urea excretion declined by a similar magnitude in all three groups. Hepatic blood flow remained unaffected, but rhGH administration increased splanchnic oxygen consumption in all groups (control, +57%*; Sepsis/SIRS, +13%; Sepsis/SIRS + Nutr +42%*; *p < 0.05 relative to corresponding basal) resulting in a decline of basal to end therapy hepatic venous oxygen saturation (control, 67 +/- 4% to 62 +/- 11%; Sepsis/SIRS, 51% +/- 14% to 43% +/- 14%*; Sepsis/SIRS + Nutr, 62% +/- 11% to 55% +/- 16%; *p < 0.05 relative to corresponding control value), suggesting that rhGH may induce centrilobular hepatic hypoxia, which may contribute to the diminished IGF-I response. CONCLUSIONS: Although critically ill patients exhibit an IGF-I increase in response to exogenous rhGH, the rise is markedly attenuated compared with healthy volunteers, indicating the presence of GH resistance. Unexpectedly, the changes in the anabolic hormone IGF-I did not appear to be related to the reduction in urea excretion. This may provide some additional evidence for IGF-I resistance. Finally, rhGH is associated with an augmented splanchnic oxygen consumption but no corresponding increase in regional blood flow. As a result, regional tissue hypoxia may arise and contribute to the impaired or suboptimal IGF-I response pattern.

Splanchnic metabolism associated with liver metastasis.

Metastatic liver disease can modify the metabolic response to critical illness. Systemic lactic acidosis may arise from an increased production due to inadequate peripheral tissue oxygen transport, altered metabolic function such as depressed pyruvate oxidation or insufficient hepatic clearing capacity due to tumor replacement of functional liver mass. Hepatic venous catheterization in a patient with extensive metastatic melanoma to the liver and adult respiratory distress syndrome indicated a marked disparity between whole body and liver oxygenation which may arise due to a markedly stepped up splanchnic oxygen utilization unmatched by a proportionate rise in regional oxygen delivery. Since some neoplasms may exhibit increased metabolic activity, it is suspected that these metastatic lesions may have contributed to the observed regional hypermetabolism thereby worsening hepatic hypoxia and exacerbating lactic acidosis. This case also illustrates the difficulties in interpreting global indicators of metabolic function and oxygenation in critically ill patients.

Central mixed and splanchnic venous oxygen saturation monitoring.

Central mixed venous oxygen saturation (SvO2) monitoring in critically ill patients to estimate adequacy of peripheral perfusion is gaining increasing popularity. However, a number of unexpected responses, one of which is marked depression of regional (splanchnic) venous oxygen saturation which may coexist with normal or high SvO2, makes interpretation of this parameter difficult. The SvO2 and hepatic venous oxygen saturation levels in seven injured (postoperative) and 15 septic patients were measured. No substantial differences between central and hepatic venous oxygen saturation was noted in nonseptic patients, however, septic subjects exhibited a normal SvO2 of 70.5% +/- 8.7% at a time when the hepatic venous saturation was 55.6% +/- 14.4% which is a significant (p less than 0.05) reduction. This reduced oxygen saturation was noted to arise from an increased regional metabolic rate rather than reduced perfusion. Nevertheless, we conclude that a flow limited regional oxygen consumption may potentially exist despite the presence of a normal SvO2 in certain patient subgroups such as septic subjects. Therefore, a normal SvO2 should not be considered as sole criteria to insure optimal oxygen delivery in critically ill patients.

Hepatic metabolic response to injury and sepsis.

BACKGROUND: Experimental reports have indicated that hepatic oxidative and synthetic metabolism may become depressed in sepsis. Because the mechanism of infection-related liver dysfunction has not been established, further study of these functional alterations could contribute to the therapeutic management of septic organ failure syndromes. However, recently controversy has arisen over the existence of these derangements that must be reconciled before further progress in this field can be made. METHODS: Splanchnic balance studies for the measurement of glucose output and oxygen consumption were used to assess hepatic function in fasted normal volunteers (n = 18), injured patients (n = 10), and patients with sepsis (n = 18). The liver's contribution to splanchnic metabolism was estimated from a comparison of splanchnic oxygen utilization in response to increases in the liver-specific process of glucogenesis. In addition, in vivo liver albumin production was determined by using the [14C] carbonate technique. RESULTS: Glucose output after injury and sepsis was increased by 12.8% and 76.6%, respectively, compared with controls. On the basis of substrate balance studies, gluconeogenesis was estimated to account for 46%, 87%, and 93%, respectively, of splanchnic glucose output in each of the three groups. In patients with sepsis glucose output was also noted to be linearly related to regional oxygen consumption, indicating that these processes were coupled and increases in the respiratory activity of the splanchnic cellular mass could be accounted for by increases in new glucose output and gluconeogenic substrate clearance. The mean albumin synthetic rate increased during injury and sepsis by 22% and 29%, respectively, compared with normal volunteers. CONCLUSIONS: These studies cast doubt on the commonly held notion that tissue respiratory dysfunction may occur during sepsis. On the contrary, hepatic function is accelerated during hyperdynamic sepsis, and evidence indicating oxidative or synthetic functional depression is lacking.

Hepatic blood flow and splanchnic oxygen consumption measurements in clinical sepsis.

In an effort to characterize the hemodynamic response of the liver to sepsis, hepatic blood flow (HBF) was measured in 10 normal volunteers and compared with that of 9 patients with sepsis. Flow was determined according to two different indicators and three methods of analysis including indocyanine green dye clearance (HBFICG), galactose clearance (GC), and galactose clearance with splanchnic galactose gradient measurement (HBFGG). For normal subjects, these three analytic methods provided essentially identical results (HBFICG = 0.74 +/- 0.18, GC = 0.72 +/- 0.14, and HBFGG = 0.76 +/- 0.16 L/min-m2). With hepatic venous sampling, HBF in patients with sepsis was significantly higher than normal levels (HBFICG = 1.28 +/- 0.50 and HBFGG = 1.17 +/- 0.52 L/min-m2) (p less than 0.025), but HBF by the GC technique (0.89 +/- 0.41 L/min-m2), which uses peripheral venous sampling, was not significantly increased because of reduced splanchnic galactose extraction, which appears to be characteristic of sepsis. Thus HBF estimates based on peripheral venous sampling must be interpreted with caution in view of the reduced extraction fraction in sepsis. HBF in clinical sepsis tends to increase in response to this inflammatory stress.

Cardiopulmonary complications after major surgery: a role for epidural analgesia?

Improvement in postoperative pulmonary mechanics with epidural analgesia has been described. Data on the hemodynamic effects of this technique are absent from the surgical literature. To provide such data we have evaluated two groups of patients undergoing aortic reconstruction: group I (n = 25), general anesthesia and group II (n = 6), general anesthesia with adjunctive epidural analgesia. The groups were comparable preoperatively as judged by the incidence of cardiac history, preoperative ejection fraction, and measured hemodynamic parameters. Postoperatively there were no significant differences in the pressure-related parameters; however, rate-related factors including heart rate and double product were significantly decreased in group II with no reduction in cardiac index. Postoperative increases in total body oxygen consumption were also markedly attenuated by epidural analgesia. Epidural analgesia reduces the hemodynamic demands on the heart after major surgery and is a useful adjunct, especially in patients with coronary artery disease.

Effects of tumor necrosis factor-alpha on glucose and albumin production in primary cultures of rat hepatocytes.

Tumor necrosis factor-alpha (TNF) is known to alter significantly in vivo hepatic glucose and albumin metabolism. However, it remains unclear whether the observed effects represent direct actions of this factor or secondary responses due to the recruitment of other mediator systems. The present study was designed to investigate direct actions of TNF on glucose and albumin production in primary cultures of rat hepatocytes. Addition of TNF to the culture medium resulted in a 45% to 50% reduction in glucose production from a control level of 239 +/- 15 nmol/plate.h. This effect was reversed by addition of anti-TNF monoclonal antibody. In glycogen-depleted cells, short-term (5-hour) incubation with TNF did not affect hepatocyte albumin secretion, which was 8.13 +/- 0.29 microgram/plate.h. However, in cells exposed to insulin or in non-glycogen-depleted cells, addition of TNF resulted in a 10% to 25% reduction in albumin production. These findings indicate that TNF exerts direct inhibitory effects on hepatocyte glucose and albumin production, but the effects on the latter process are modest. A notable aspect of the findings is that the albumin effects are insulin or glucose substrate-dependent, which may have implications regarding liver function during nutritional support in critical illness.

Oxygen transport-dependent splanchnic metabolism in the sepsis syndrome.

OBJECTIVE: Total body oxygen consumption (VO2) may be pathologically oxygen delivery (DO2)-dependent in critically ill patients exhibiting the sepsis syndrome. This observation has been used to infer the presence of occult tissue or organ ischemia that potentially can be eradicated by augmenting DO2. We examined this hypothesis by determining the VO2-DO2 relationship and lactate metabolism in the splanchnic region. DESIGN: Before and after intervention trial. SETTING: University-affiliated Veterans Affairs Medical Center, Allen Park, Mich. PATIENTS: Eighteen surgical patients exhibiting the sepsis syndrome. INTERVENTION: Systemic and splanchnic oxygen exchange and lactate uptake measurements before and after augmentation of DO2 with blood transfusion. MAIN OUTCOME MEASURES: Changes in oxygen exchange and lactate metabolism. RESULTS: The splanchnic VO2 index rose 9% in association with a 26% regional DO2 index increase indicating an oxygen transport dependency (P < .05). Splanchnic O2 extraction (0.47 +/- 0.04) was significantly greater than the mean systemic level (0.31 +/- 0.02) and showed a greater decline following DO2 index augmentation (0.41 +/- 0.04 vs 0.28 +/- 0.03, respectively). However, splanchnic lactate uptake was not changed significantly in response to the increased DO2 index. CONCLUSIONS: Although splanchnic oxygen transport dependency and elevated extraction ratios suggest the presence of regional ischemia that should be relieved with an increased DO2 index, the observed changes in lactate uptake do not support this conclusion. The significance of the VO2-DO2 relationship, its role in the pathophysiology of the sepsis syndrome, and its place in the clinical care of the septic surgical patient are in doubt.

Insulinlike growth factor 1 production is inhibited in human sepsis.

We studied the response of 14 normal volunteers and five septic patients to a 48-hour course of exogenous biosynthetic human growth hormone (hGH) or placebo. Six normal controls (group 1) received saline, eight normal controls received hGH (group 2), and five septic patients also received biosynthetic hGH (group 3). Urinary urea excretion declined, and splanchnic amino acid uptake was maintained only in group 2 subjects. Septic patients exhibited changes in amino acid and urea dynamics comparable to those of subjects receiving placebo. Insulinlike growth factor 1 (IGF-1) production and plasma concentrations increased in group 2 in a fashion corresponding to the changes in nitrogen exchange, whereas septic patients exhibited no change in IGF-1 level. Therefore, in this septic patient group, exogenous hGH was ineffective in attenuating nitrogen losses and stimulating IGF-1 production. This supports the hypothesis that IGF-1 is a mediator of the anabolic effect of hGH.

The relationship of insulin production to glucose metabolism in severe sepsis.

Basal glucose metabolism was evaluated in eight stable, infected patients by measuring hepatic glucose production rates in relation to stress endocrine profile and by comparing these data to five injured, noninfected patients. All patients exhibited normal total-body oxygen consumptions and cardiac indices. Fasting basal insulin values were similar in both groups (6 microU/cc) despite a significantly higher plasma glucose level in septic patients (106 +/- 14 mg/dL) compared to nonseptic patients (88 +/- 10 mg/dL). Septic patients exhibited splanchnic glucose production and calculated glucose clearance rates, 53% and 34% higher, than injured nonseptic patients, respectively. In addition, septic patients exhibited a decreased pancreatic insulin secretory response to an intravenous glucose tolerance test as evidenced by a significantly depressed peak insulin value (17 microU/cc) relative to injured patients (77 microU/cc). These findings indicate that insulin suppression is evident in sepsis even in the absence of shock and suggest that sepsis-related basal hyperglycemia does not appear to be associated with peripheral insulin resistance.

Endocrine mediators of metabolism associated with injury and sepsis.

We have studied the endocrine characteristics of 13 seriously ill patients with the use of a provocative intravenous glucose bolus. Notable in this stressed patient population was that no major interpatient differences in response to glucose were found for insulin, glucagon, cortisol, or epinephrine. However, following glucose challenge half of this group (7/13) exhibited a prominent "paradoxical" mean human growth hormone (hGH) elevation (26.4 +/- 9.3 microU/ml) whereas the others (6/13) exhibited only a minor increase (7.8 +/- 2.9 microU/ml). In addition, norepinephrine levels were significantly higher in the latter group suggesting that the adrenergic nervous system plays a major role in regulating hGH in stress.

Altered immunologic function and nitrogen metabolism associated with depression of plasma growth hormone.

The specific role of endogenous growth hormone in regulating nitrogen metabolism during surgical stress and infection remains unclear. We have studied splanchnic amino acid uptake and plasma concentrations in patient groups exhibiting growth hormone hypersecretion or relative growth hormone depression in response to stress. Splanchnic amino acid uptake was similar in both groups although plasma levels were significantly higher in the presence of depressed growth hormone production suggesting increased net peripheral proteolysis. In association with this latter observation. T lymphocyte subset analysis revealed a greater incidence of depressed helper to suppressor cell ratios in the presence of depressed growth hormone suggesting a greater impairment of cellular immunity.

Altered T-lymphocyte subsets in severe sepsis.

To investigate the immune response of surgical patients to injury and sepsis, we measured total lymphocyte counts and T-cell subsets in five nonseptic and 17 septic subjects. Total lymphocyte and T-cell levels declined to similar degrees following injury or sepsis and did not appear to be of value as prognostic indicators. However, analysis of T-cell subsets in septic patients indicated that survivors exhibited normal T-cell subpopulations as well as helper to suppressor cell ratios. Nonsurvivors generally exhibited a selective depression of helper (OKT4) T-cells and the resultant degree of helper to suppressor ratio decline was directly related to mortality. A helper to suppressor ratio (OKT4/T8) below 0.6 was uniformly associated with a fatal outcome. Finally, a small subgroup of septic nonsurviving patients exhibited a selective depression of suppressor (OKT8) lymphocytes which also appeared to carry an unfavorable prognosis. These data indicate that T-lymphocyte subpopulation analysis is a useful predictor of hospital course.

The significance of hypoalbuminemia following injury and infection.

Serum albumin and absolute hepatic albumin synthetic rates were measured in ten seriously ill injured and septic patients using the (14C) carbonate technique. Although it is commonly believed that serum albumin levels (SAL) reflect hepatic function and visceral protein status in hospitalized patients, no relationship was found between these two measured parameters in this patient population. A depressed mean serum albumin level of 1.98 +/- 0.50 gm/dl (range: 1.25-2.69 gm/dl) was associated with a supranormal mean albumin synthetic rate of 215 +/- 121 mg/kg/day (range: 21-447 mg/kg/d). No significant mean SAL and albumin synthetic rate differences were noted between injured nonseptic and septic patient populations. Since albumin synthesis was elevated in most of these stressed patients these findings support the view that extravascular protein redistribution and/or increased peripheral catabolism are the major factors responsible for hypoalbuminemia in critically ill patients.

Patient-controlled analgesia versus intermittent analgesia dosing.

Actively involving the patient in his or her own pain management by using patient-controlled analgesia (PCA) during the postoperative period is a concept recently introduced. This method allows self-administration of small, frequent doses of an analgesic agent to maintain a state of constant pain control. We studied the relative efficacy of PCA compared with intermittent analgesic dosing in 16 male patients requiring posterolateral thoracotomy. Eight patients received intermittent doses of buprenorphine hydrochloride (0.3 mg intramuscularly every 3 to 6 hours), and eight patients were allowed to self-activate a PCA device according to a designed protocol. In the patients using PCA, a significant reduction in the postoperative pulmonary complication rate, as evidenced by radiographic findings, was noted. In addition, significantly less medication was used and postoperative fever was substantially reduced in the PCA group. We believe PCA to be a safe, effective, and beneficial pain management modality that deserves attention in the postoperative period.

Management of multiple enterocutaneous fistulas.

Enterocutaneous fistulas present a difficult management problem in the intensive care unit. Although some patients require surgical intervention for fistula control, key elements to good clinical management include mechanical control and vigorous nutritional support. This approach includes eradication of malnutrition, support of the hypercatabolic state, and maintenance or replacement of protein loss from fistula drainage. Good mechanical control involves integument protection and a mechanism of drainage collection. The patient we describe taxed the ingenuity and creativity of all those concerned with his care. Modification of a previously described technique to protect surrounding skin and collect fistula output served as a simple and inexpensive approach to eliminate infection potential, improve the patient's comfort, and decrease the nursing time that would have been required for frequent, complex dressing changes.

Filling the waiting time in the clinic with education about glaucoma.

The purpose of this study was to examine the effects of an educational intervention, designed to occupy the waiting time in an eye clinic, on learning about glaucoma and patient satisfaction. Subjects (N = 100) waiting in the eye clinic were randomly assigned to 2 groups: (1) educational intervention and (2) usual clinic care (no structured education during the waiting time in the clinic). Patients who were taught in the clinic had significant gains in knowledge about glaucoma from pretest to posttest and were more satisfied with the education received during the visit.