Hypoplastic left heart syndrome

Study objectives: Recent data indicate that increases in inflammatory cytokines are seen in patients with diverse cardiac diseases. However, the primary stimulus for cytokine secretion during cardiac illness remains unknown. Since bacterial endotoxin is a potent inducer of cytokines, we determined the incidence, magnitude, and clinical relevance of endotoxemia in children with congenital heart disease before and after surgical repair.

Design: A prospective, observational study.

Setting: A large, urban, university-affiliated, tertiary-care children's hospital.

Patients: Thirty children with a variety of congenital heart defects (median age, 59 days; median weight, 4.0 kg) were sequentially enrolled.

Interventions: Blood was sampled prior to surgery, and at 1, 8, 24, 48, and 72 h following cardiopulmonary bypass. Assays included plasma endotoxin, lipopolysaccharide-binding protein (LBP), and interleukin-6 (IL-6).

Measurements and results: Twenty-nine of 30 patients (96%) had evidence of endotoxemia during the study period. Twelve of the 30 patients (40%) were significantly endotoxemic prior to surgery. LBP, a plasma marker that responds to bacteria and endotoxin, rose significantly following cardiopulmonary bypass, as did the plasma levels of IL-6. Fifteen of 30 patients met prospectively defined criteria for experiencing a severe hemodynamic disturbance in their postoperative course. These patients had significantly higher preoperative plasma LBP (p [is less than] 0.02) and plasma endotoxin levels (p [is less than] 0.05), compared to patients with less-severely disturbed hemodynamics. Mortality was 25% in patients with preoperative endotoxemia, compared with no mortality in patients who were not endotoxemic before surgery (p = 0.05).

Conclusions: These data demonstrate that endotoxemia in children with congenital heart disease is more common than previously suspected, and is associated with clinical outcomes. We conclude that clinical trials targeting endotoxin will be necessary to determine if endotoxin is a causal, etiologic agent in the disease process.

(CHEST 2000; 117:1706-1712)

Key words: cardiopulmonary bypass; congenital heart disease; endotoxin; lipopolysaccharide-binding protein

Abbreviations: CPB = cardiopulmonary bypass. DHCA = deep hypothermic circulatory arrest; ELISA = enzymelinked immunosorbent assay; EU = endotoxin units; IL-6 = interleukin-6; LBP = lipopolysaccharide-binding protein; LPS = lipopolysaccharide; TNF-[Alpha] = tumor necrosis factor-[Alpha]

Studies indicate that increases in proinflammatory cytokines are seen in patients with diverse cardiac diseases, including congestive heart failure, cardiomyopathy, and myocarditis.[1-4] For example, the cytokine tumor necrosis factor-[Alpha] (TNF-[Alpha]) is synthesized by human cardiac myocytes, and the level of TNF-[Alpha] expression correlates with the degree of cardiac dysfunction in patients.[5-7] In animals, synthesis of TNF-[Alpha] by the heart is itself sufficient to cause cardiomyopathy and lethal cardiac failure.[8,9] Furthermore, early human trials have demonstrated that antagonism of TNF-[Alpha] improves cardiac failure in humans with New York Heart Association class III heart failure or idiopathic dilated cardiomyopathy.[10,11] However, despite growing evidence that cytokines such as TNF-[Alpha] may be critically involved in the pathogenesis of cardiac diseases, the primary stimulus for cytokine secretion remains unknown.

Bacterial endotoxin, or lipopolysaccharide (LPS), is a primary inducer of TNF-[Alpha] production during sepsis.[12-15] With respect to cardiac diseases, the role of endotoxin has been examined primarily in the context of cardiopulmonary bypass (CPB), driven by the hypothesis that endotoxin may be present in the extracorporeal circuit, or may be translocated across the intestine secondary to nonpulsatile, low-flow perfusion.[16,17] These studies have generally demonstrated only transient low-level endotoxemia during CPB, with rapid resolution following completion of CPB in the majority of patients.[18-21]

In this study, we examined the potential role of endotoxin in the pathogenesis of cardiac dysfunction in children with severe congenital heart disease, both prior to and following CPB. In addition, we also measured the plasma levels of lipopolysaccharide-binding protein (LBP),[22-24] which increases in response to exposure to bacteria and their endotoxin.[25] In contrast to LPS, LBP is a plasma protein with a relatively long half-life, and can be reliably assayed by enzyme-linked immunosorbent assay (ELISA). We postulated that measurement of both LPS and LBP would provide a more accurate estimation of the prevalence of endotoxemia and its potential significance to the management of children undergoing therapy for congenital heart disease.

MATERIALS AND METHODS

Design and Sample

The protocol, approved by the Institutional Review Board at the University of Texas Southwestern Medical Center, was an unblinded, prospective, observational study in which 30 children with severe congenital heart disease were sequentially enrolled while awaiting surgical repair and/or palliation. One patient with hypoplastic left heart syndrome died intraoperatively; therefore, data on this child are included only in the preoperative analysis. Patients with clinical evidence of preoperative infection were excluded from the study.

Anesthesia

Anesthesia was induced with sevoflurane, nitrous oxide, and oxygen; intubation was facilitated with IV rocuronium and fentanyl. Anesthesia was maintained with fentanyl, 30 to 50 [micro]g/kg, isoflurane, and pancuronium. Nine patients received tranexamic acid, 50 to 100 mg/kg, and three patients received aprotinin (dosed to achieve 350 U/mL total blood volume).

CPB

The extracorporeal circuit consisted of a roller pump (Cobe Perfusion System Heart-Lung Machine; Cobe Cardiovascular; Arvada, CO), membrane oxygenator (MicroOxygenator System; Polystan; Copenhagen, Denmark), and cardiotomy filters (Hemcor 400; Minntech; Plymouth, MN). Prior to the institution of CPB, the patients' blood was anticoagulated with heparin, 300 U/kg. Fifteen patients underwent deep hypothermic circulatory arrest (DHCA; core temperature, 16 to 18 [degrees] C), and the remainder were cooled to a core temperature of 25 to 30 [degrees] C for the completion of surgery. Hemofiltration was performed prior to completion of CPB on all patients in an attempt to remove excess free water and attain a hemoglobin [is greater than] 12 g/dL.

Blood Sampling

Blood samples for the determination of LPS, LBP, and interleukin-6 (IL-6) were obtained prior to surgery and 1, 8, 24, 48, and 72 h after completion of CPB. The preoperative sample was obtained from a newly placed central venous catheter, immediately after the induction of anesthesia and endotracheal intubation. For determination of endotoxin levels, blood samples were collected into heparinized Vacutainer tubes (Becton-Dickson; Rutherford, NJ) selected for low endotoxin content (Bio-Whitaker; Walkersville, MD), immediately placed on ice, and walked to the laboratory by an investigator. Platelet-rich plasma was obtained by centrifugation (180g, 10 min, 2 to 8 [degrees] C). Samples were stored at - 70 [degrees] C until assay.

LPS, LBP, and IL-6 Assays

All assays were done in a blinded fashion. The level of LPS in the platelet-rich plasma was determined by using a kinetic chromogenic Limulus amebocyte lysate assay (Endochrome-K; Endosafe; Charleston, SC) according to the instructions of the manufacturer. LPS concentrations are expressed in terms of endotoxin units (EU) per milliliter relative to an Escherichia coli O55:B5 control standard endotoxin. In normal plasma, endotoxin levels are typically [is less than] 0.2 EU/mL. LBP levels were determined by ELISA as originally described.[26] IL-6 was measured using a sandwich ELISA (R&D Systems; Minneapolis, MN).

Postoperative Myocardial Dysfunction

A severe (vs less-severe) postoperative course was prospectively defined in two ways: perioperative death, or a net positive fluid balance of [is greater than] 40 mL/kg in the first 24 h postoperatively and an inotropic support score of [is greater than] 12 during the study period. The inotropic support score was calculated as described by Wernovsky et al.[27] Specifically, each 1.0 [micro]g/kg/min of dopamine or dobutamine, and each 0.01 [micro]g/kg/min of epinephrine yielded a score of 1. Postoperative severity of illness was scored prior to knowledge of LPS, LBP, or IL-6 values.

Statistical Analysis

All statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS; Chicago, IL). Wilcoxon signed rank tests for nonparametric data were performed to determine if a significant rise in LPS, LBP, or IL-6 had occurred postoperatively. A Mann-Whitney test for nonparametric data was performed to determine if there was a significant difference in LPS or LBP concentrations between the patients who had a more severe clinical course, compared to those with a less-severe clinical course. The [chi square] test procedure for nonparametric data was used to compare gender, myocardial dysfunction scores, diagnosis, and type of surgical repair between the following two groups: those who had elevated levels of endotoxin prior to CPB (group 1), and those who did not (group 2). All data are graphically presented as mean [+ or -] SEM.

RESULTS

The 30 enrolled children ranged in age from 4 to 402 days (median age, 59 days), and in weight from 2 to 9.5 kg (median weight, 4 kg). The genders, ages, cardiac diagnoses, and surgical repairs are listed in Table 1. No patients were excluded from enrollment because of the clinical suspicion of sepsis. There were 15 patients each in the severe and less-severe myocardial dysfunction groups. One patient in each severity group required inotropic support preoperatively, with both patients receiving 5 [micro]g/kg/min of dobutamine.

(*) Data are presented as No.

TAPVR = total anomalous pulmonary venous return;

RVOT = right ventricular outflow tract.

Twenty-nine of the 30 patients (96%) had evidence of endotoxemia during the study period, either by detection of LPS directly or by detection of an LBP plasma level [is greater than] 2 SDs above the mean for healthy adults.[25] The LPS, LBP, and IL-6 levels for all patients are displayed in Figures 1-3. To better elucidate endotoxin kinetics, we classified patients into two groups: those who had elevated levels of endotoxin prior to CPB (group 1), and those who did not (group 2). The demographics of each of these groups are listed in Table 1. There were no significant differences in age, weight, anatomic diagnosis, and preoperative location (pediatric or neonatal ICU vs newborn nursery or admission from home) or severity of postoperative myocardial dysfunction between these two groups. [chi square] or Mann-Whitney statistical tests were used to compare the groups as appropriate.

[Figures 1-3 ILLUSTRATION OMITTED]

Prior to CPB, 12 patients had significant elevation of plasma endotoxin. Eight of these 12 patients had cyanotic lesions, 2 had left-sided obstructive lesions, and 2 had significant congestive heart failure. None of the patients with preoperative endotoxemia were receiving inotropic support prior to surgery. In these patients (group 1), endotoxin tended to decline following completion of CPB (Fig 1, middle); endotoxin levels remained abnormally elevated throughout the study period. In those children without preoperative endotoxemia (group 2), the level of plasma endotoxin rose significantly following bypass, achieving a peak value at 1-h postbypass, and remaining significantly elevated thereafter (Fig 1, bottom).

There was a transient but significant decrease in plasma LBP immediately after completion of CPB and hemofiltration. Thereafter, a highly consistent and statistically significant rise in LBP occurred (Fig 2), which was similar for patients in both groups 1 and 2. Similarly, there was a significant rise in IL-6 at all time points in both groups 1 and 2 following CPB (Fig 3).

Finally, we determined whether children who experienced a severe hemodynamic disturbance in their postoperative course, defined prospectively, might differ from less-severe patients when preoperative LPS and LBP levels were compared. In this comparison, the more severely ill children had significantly higher preoperative plasma LBP (p [is less than] 0.02; Fig 4, top) and preoperative LPS (p [is less than] 0.05; Fig 4, bottom), compared to patients who experienced a less-severe postoperative course. However, preoperative IL-6 levels were statistically similar for both groups (p = 0.45). Furthermore, of the 12 patients who were endotoxemic prior to surgery, there were three deaths (25%), compared to no deaths in the 18 patients who were not endotoxemic prior to surgery (p = 0.05). None of the three patients who died were in the pediatric ICU prior to surgery. One patient, who underwent a Damus-Kaye-Stansel procedure for a double-outlet right ventricle, was at home prior to surgery. The other two patients went to the operating room from the newborn nursery, one with hypoplastic left heart syndrome and one with total anomalous pulmonary venous return.

[Figure 4 ILLUSTRATION OMITTED]

Patients in the severe myocardial dysfunction group tended to be younger and smaller, and underwent more significant surgical repairs than those in the less-severe group. Median age and weight in the severe group were 10 days and 3.7 kg, compared to the less-severe group where median age and weight were 120 days and 5.5 kg. The majority of infants having total anomalous pulmonary venous return repair, arterial switch operation and Norwood procedure, for example, were in the severe myocardial dysfunction group. Ten of 15 patients in the severe myocardial dysfunction group underwent a period of DHCA, as opposed to 5 of 15 in the less-severe group. However, there was no correlation between the length of DHCA or CPB and LPS, LBP, or IL-6 levels.

DISCUSSION

Endotoxin, the highly inflammatory surface component of Gram-negative bacteria, has been previously implicated in the morbidity and mortality of a number of clinical settings, including patients undergoing cardiac surgery. However, the potential involvement of endotoxin in other aspects of cardiac disease is less clear, as persistent endotoxemia in patients with cardiac disease has not been conclusively demonstrated.[18-21] Our data presented here indicate that the majority of children with severe congenital heart disease have direct and indirect evidence of endotoxemia perioperatively, and that 40% are significantly endotoxemic prior to surgical repair. Niebauer et al[28] reported elevated levels of plasma endotoxin in adults with edematous chronic congestive heart failure, although elevated levels of LBP or anti-LPS autoantibodies were not observed in this patient population. Our data are the first to suggest that detection of LPS and/or LBP has prognostic significance in any primary cardiac disease. If endotoxin contributes to cardiac dysfunction during chronic heart failure or following cardiac surgery, drugs directed against endotoxin may therefore be useful adjunctive therapy to improve morbidity and mortality.

The incidence and degree of endotoxemia in children with congenital heart disease preoperatively was unsuspected, and previously undocumented. These data may be explained by the more complex congenital lesions in our patients, compared to those in previous publications, or by differences in the performance of endotoxin assays. One would have expected that endotoxemia would reflect severity of preoperative illness, but this was not the case in the current study, as the patients with preoperative endotoxemia were clinically indistinguishable from those without preoperative endotoxemia prior to surgery. This is underscored by the fact that both patients who required inotropic support prior to surgery did not have preoperative endotoxemia. The patients who were endotoxemic preoperatively required more therapeutic interventions postoperatively and experienced a higher mortality rate. Why these patients were endotoxemic, and how long they were endotoxemic, cannot be answered by this study protocol. However, no patient had clinical evidence of preoperative infection. It is possible that these children may have had intestinal ischemia due to low systemic cardiac output, or intestinal hypoxia due to relatively normal intestinal perfusion with cyanotic arterial blood. Either of these factors could be associated with increased intestinal permeability and translocation of bacterial endotoxin and other bacterial products. Indirect support for this hypothesis is the fact that term infants with congenital heart lesions suffer a relatively high incidence of necrotizing enterocolitis while awaiting cardiac surgery.[29,30]

The underlying biology of perioperative endotoxemia was clarified by classifying those patients who were or were not endotoxemic preoperatively. In patients who were endotoxemic preoperatively, endotoxin levels initially fell following CPB, but remained abnormally elevated throughout the study period. This initial decrease may have been secondary to a dilution effect of CPB, given the infants' small blood volumes, or perhaps due to clearance of endotoxin by hemofiltration prior to completion of CPB.[31] It is also possible that these patients, who were endotoxemic preoperatively, may have induced and enhanced mechanisms for endotoxin clearance, compared to patients who were not endotoxemic preoperatively.[32-34]

In contrast, patients who were not endotoxemic preoperatively demonstrated a significant elevation of plasma endotoxin at 1 h and 8 h after CPB, compared to baseline. A number of factors may explain this endotoxemia during CPB. First, there are many sources of endotoxin, including the extracorporeal circuit, infusion solutions, drugs, and surgical materials.[18] More importantly, increased intestinal permeability during CPB has been documented in adult patients, allowing for bacterial translocation and release of endotoxin into the circulation.[16] Measures such as pulsatile perfusion or higher flow during bypass to improve intestinal perfusion, and aggressive antibiotic regimens to decrease intestinal bacterial load prior to bypass have resulted in lower plasma LPS levels.[35,36] In adults undergoing coronary artery bypass grafts, low levels of antibodies to endotoxin preoperatively were associated with an increased risk of postoperative complications.[37]

IL-6 was measured because it is generally considered a nonspecific marker of inflammation. It has been shown to increase with endotoxemia, trauma, autoimmune disease, and following CPB.[17,38-40] IL-6 levels were normal in all patients prior to CPB, peaked much earlier, and fell more quickly than LBP measures. There were no statistically significant differences in the IL-6 levels among the different groups of patients. These results indicate that IL-6 has a much shorter half-life than LBP, and that its increase may be due to CPB alone.

CONCLUSION

This study is the first to measure LBP in children with congenital heart disease, and among the first to measure LBP in children with any diagnosis. More importantly, our results indicate that LBP elevations have prognostic significance in these patients, as has been reported for other patient populations.[25] We measured LBP because of its sensitivity and reported specificity as a marker for exposure to bacteria or their endotoxin, as well as its ease and reliability of assay by conventional ELISA. Those patients who required a higher level of postoperative support had significantly higher preoperative plasma levels of LBP. These data support the relative utility of LBP assays compared to LPS assays, and suggest that plasma LBP should be formally studied in larger trials as a predictor of postoperative severity of illness. Furthermore, the highly consistent rise in LBP following CPB again implicates the presence of endotoxin, and suggests that LBP could serve as a useful surrogate marker in clinical trials aimed at inhibition of endotoxin activity.

Finally, this is the first report to suggest that there is an association between evidence of preoperative endotoxemia and clinical outcome. Our data suggest that the plasma concentration of LPS may serve as a prognostic marker in children undergoing repair of congenital cardiac disease. However, clinical trials targeting endotoxin will be necessary to determine if endotoxin is a causal, etiologic agent in the disease process.

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Laurance L. Lequier, MD; Hisashi Nikaidoh, MD; Steven R. Leonard, MD; Joni L. Bokovoy, DrPH; Mark L. White, BA; Patrick J. Scannon, MD, PhD; and Brett P. Giroir, MD

(*) From the Department of Pediatrics (Drs. Lequier, Bokovoy, and Giroir), The University of Texas Southwestern Medical Center, Dallas, TX; the Division of Pediatric Cardiothoracic Surgery (Drs. Nikaidoh and Leonard), Children's Medical Center, Dallas, TX; and XOMA (US) LLC (Mr. White and Dr. Scannon), Berkeley, CA.

Mr. White and Dr. Scannon are employed by XOMA Corporation, which has developed a biologic agent (r[BPI.sub.21]) for the purpose of clearance and neutralization of endotoxin. This agent is in Phase III clinical trials. The involvement of XOMA Corporation in this protocol was blinded and limited to assay of blood

Manuscript received March 18, 1999; revision accepted January 19, 2000.

Correspondence to: Brett P. Giroir, MD, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas TX 75235-9063; e-mail: Brett. Giroir@email.swmed.edu

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