Endotoxaemia during left ventricular assist device insertion: relationship between risk factors and outcome

C. M. N. O’Malley*,1, R. J. Frumento1, B. Mets1, Y. Naka2 and E. Bennett-Guerrero1

1 Department of Anaesthesiaand 2 Department of Surgery, Columbia University College of Physicians and Surgeons, 630, West 168th Street, New York, NY 10032, USA

*Corresponding author. E-mail: cathomalley@hotmail.com

Accepted for publication: August 13, 2003


    Abstract
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Background. Endotoxaemia, caused by splanchnic ischaemia during surgery, is believed to trigger systemic inflammation and cause postoperative organ dysfunction. A relationship between the plasma concentration of endotoxin during surgery and known risk factors for postoperative morbidity and mortality (e.g. age, abnormal gastric tonometric variables) and adverse outcome after surgery has not been demonstrated.

Methods. In a prospective study, the plasma concentration of endotoxin was measured in 12 patients undergoing implantation of a left ventricular assist device. Automated air gastric tonometry was performed in all patients. The relationship between plasma endotoxin concentration, risk factors, and postoperative outcome was explored.

Results. Carbon dioxide gap increased from 0.7 (0.3) to 3.6 (1.6) kPa at the end of surgery. Endotoxin was detected in one of 12 patients at baseline and in nine of 12 patients at the end of surgery (P=0.003). A high plasma concentration of endotoxin at the end of surgery was associated with a higher carbon dioxide gap (r=0.59, P<0.05), and a higher postoperative multiple organ dysfunction score (r=0.7, P=0.01).

Conclusions. The finding of an association between high intraoperative plasma concentrations of endotoxin, abnormal gastric tonometric variables and adverse outcome supports the view that endotoxaemia is caused by gut hypoperfusion during surgery and is associated with postoperative organ dysfunction.

Br J Anaesth 2004; 92: 131–3

Keywords: complications, endotoxaemia; heart, left ventricular assist device; measurement techniques, gastrictonometry; surgery, cardiac


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Splanchnic ischaemia during surgery may cause leakage of bacterial endotoxin into the systemic circulation, triggering systemic inflammation, and postoperative organ dysfunction.1 An abnormal gastric PCO2 to arterial PCO2 difference may be a marker of splanchnic ischaemia and has been associated with adverse outcomes after cardiac,2 and non-cardiac surgery.3

The implantable left ventricular assist device (LVAD) was developed to provide circulatory support for patients awaiting heart transplantation. However, LVAD insertion is associated with significant morbidity and mortality.4 Given the high incidence of postoperative organ dysfunction, this patient population serves as a model for the study of intraoperative risk factors and outcome. We measured the plasma concentration of endotoxin in patients undergoing LVAD implantation, and explored the relationship between these levels, and risk factors and outcome.


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Institutional Review Board approval and written informed consent were obtained. Twelve adult patients undergoing implantation of a HeartMate® LVAD (Thoratec Corporation, Pleasanton, CA, USA) were enrolled in a prospective, observational study. Other, unrelated data regarding cardiac output measurement during LVAD implantation were collected from these patients and have been reported elsewhere.5 Anaesthesia was induced and maintained with a combination of midazolam, etomidate, fentanyl, isoflurane, and rocuronium. Patients were not pre-treated with H2 antagonists. Intra-arterial pressure, pulmonary artery pressures, and transoesophageal echocardiography were monitored in all patients. All patients underwent standard, non-pulsatile, moderate hypothermic (32°C) cardiopulmonary bypass.

Gastric tonometric variables were obtained by automated air tonometry according to the manufacturer’s instructions (Datex-Ohmeda, Tewksbury, MA, USA). The PgCO2PaCO2 difference (carbon dioxide gap) was calculated after induction of anaesthesia (baseline) and at the end of surgery. At the same time-points, arterial blood was sampled for plasma endotoxin measurement. Clinicians were blinded to the gastric tonometric data.

Plasma endotoxin concentrations were determined in serial dilutions of plasma from each patient using the established limulus amebocyte lysate assay, according to the manufacturer’s instructions (Associates of Cape Cod, MA, USA, assay sensitivity=0.25 endotoxin u ml–1 (EU ml–1)).6 All samples were assayed on a single day. The individual performing the endotoxin assays was blinded to all the clinical and tonometric data.

Organ function was assessed on postoperative day three using the established multiple organ dysfunction (MOD) score, which is a direct measure of organ dysfunction and morbidity, predictive of hospital mortality.7 Postoperative day three was selected for calculation of the MOD score as the interpretation of clinical and laboratory variables in the immediate postoperative period may be confounded by factors such as haemodilution, sedation, and mechanical ventilation. There may also be a delay in development of organ dysfunction after surgery.

Data were tested for normality. Mann–Whitney or t-tests were then used to compare baseline values with end of surgery measurements. Proportions were analysed using Fisher’s exact test. The small sample size precluded a multivariate analysis. Associations between the end of surgery plasma endotoxin concentration and other variables were tested using Spearman rank correlation. A P-value of <0.05 was considered significant. Data are presented as mean (SD) (range) unless otherwise stated.

Cardiac index increased from 1.9 (0.7) (1.1–3.5) litre min–1 m–2 at baseline to 3.0 (0.8) (1.8–4.3) litre min–1m–2 at the end of surgery (P<0.0001). Cardiac index at the end of surgery reflects flow through the implanted LVAD. The carbon dioxide gap was increased from 0.7 (0.3) (0.3–1.0) kPa at baseline to 3.6 (1.6) (1.0–6.0) kPa at the end of surgery (P<0.0001). The carbon dioxide gap was normal (<1.5 kPa) at baseline in all (12/12) patients but was normal in only one patient at the end of surgery (P<0.0001). Plasma endotoxin concentration (median (range)) at the end of surgery was 12.5 (0–125) EU ml–1. Endotoxaemia (concentration >2.5 EU ml–1) occurred in one of 12 (8%) patients at baseline and nine of 12 (75%) patients at the end of surgery (P=0.003) (Fig. 1). A higher concentration of endotoxin at the end of surgery was associated with a higher carbon dioxide gap (r=0.59, P<0.05), a higher norepinephrine dose (r=0.63, P=0.03), and a higher MOD score (r=0.7, P=0.01) (Table 1).



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Fig 1 Individual plasma endotoxin concentration (EU ml–1) at baseline and at the end of surgery in 12 patients undergoing LVAD insertion. EOS=end of surgery.

 

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Table 1 Correlation between plasma concentration of endotoxin at the end of surgery risk factors for adverse outcome after cardiac surgery, and postoperative outcomes (n=12). Carbon dioxide gap=gastric partial pressure of carbon dioxide–arterial partial pressure of carbon dioxide
 

    Comment
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
In this prospective study, a correlation was observed between high plasma concentration of endotoxin and high carbon dioxide gap during surgery, and organ dysfunction after LVAD insertion. We are aware that this study is limited by its small sample size precluding a multivariate analysis and that no observational study can prove a causal relationship. However, our findings support the view that endotoxaemia is caused by gut hypoperfusion during surgery and is associated with postoperative morbidity in high-risk patients.

The clinical significance of endotoxaemia during surgery has been questioned. However, there is some evidence to suggest that endotoxaemia contributes to the development of postoperative morbidity in surgical patients.2 Seventy-five per cent of patients in our study developed endotoxaemia at the end of surgery. Furthermore, higher plasma concentrations of endotoxin were associated with a higher postoperative MOD score, suggesting a relationship between endotoxaemia and adverse outcomes after LVAD implantation. This finding is of particular interest as LVAD recipients have a high incidence of postoperative renal failure, hepatic dysfunction, and haematological abnormalities,4 which could be caused by endotoxin-mediated systemic inflammation.1

Endotoxaemia during surgery is thought to be caused by splanchnic ischaemia. The most accurate, clinically applicable reflection of splanchnic ischaemia is thought to be the carbon dioxide gap, which is regarded as indicative of an imbalance between gastric perfusion, metabolism, and alveolar ventilation.8 An abnormal carbon dioxide gap developed in 11 of the 12 study patients, indicating that gut ischaemia is common in LVAD recipients. Additionally, a high plasma concentration of endotoxin was associated with a high carbon dioxide gap at the end of surgery. To our knowledge, this is the first study to demonstrate such an association, supporting the hypothesis that endotoxaemia during LVAD implantation is caused by splanchnic ischaemia.

Multiple factors, including low cardiac output, hypovolaemia, and endogenous and/or exogenous splanchnic vasoconstrictors, may contribute to the development of splanchnic ischaemia and endotoxaemia in LVAD recipients. Of note, endotoxaemia occurred in our study patients despite an improvement in systemic blood flow after LVAD implantation. Therefore, it appears that factors other than isolated low cardiac output impact on splanchnic perfusion and endotoxin leakage during LVAD surgery.

High doses of exogenous vasoconstrictors are commonly administered during and after separation from cardiopulmonary bypass after LVAD implantation.9 We found an association between the administration of higher doses of norepinephrine and higher plasma concentrations of endotoxin at the end of surgery. This may reflect a vasoconstrictor-mediated, cardiac output-independent, redistribution of blood flow at the microcirculatory level that results in gut ischaemia and endotoxaemia. It is also possible however that endotoxaemia is responsible for the vasodilatation and subsequent hypotension and norepinephrine requirement.

In summary, our findings suggest that endotoxaemia is caused by gut hypoperfusion during surgery and is associated with postoperative morbidity in LVAD recipients. Larger prospective, controlled studies are necessary to confirm our findings and to determine whether interventions to prevent or treat splanchnic ischaemia in high-risk cardiac surgical patients inhibit endotoxaemia and are associated with an improvement in outcome.


    References
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Bennett-Guerrero E. Systemic Inflammation. In: Kaplan JA, Reich DL, Konstadt SN, eds, Cardiac Anesthesia. Philadelphia: W.B. Saunders, 1998; 297–318

2 Bennett-Guerrero E, Panah MH, Bodian CA, et al. Automated detection of gastric luminal partial pressure of carbon dioxide during cardiovascular surgery using the Tonocap. Anesthesiology 2000; 92: 38–45[CrossRef][ISI][Medline]

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4 Oz MC, Argenziano M, Catanese KA, et al. Bridge experience with long-term implantable left ventricular assist devices. Are they an alternative to transplantation? Circulation 1997; 95: 1844–52[Abstract/Free Full Text]

5 Mets B, Frumento RJ, Bennett-Guerrero E, Naka Y. Validation of continuous thermodilution cardiac output in patients implanted with a left ventricular assist device. J Cardiothorac Vasc Anesth 2002; 16: 727–30[CrossRef][ISI][Medline]

6 Travedi B, Valerio C, Slater JE. Endotoxin content of standardized allergen vaccines. J Allergy Clin Immunol 2003; 111: 777–83[CrossRef][ISI][Medline]

7 Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23: 1638–52[ISI][Medline]

8 Chapman MV, Mythen MG, Webb AR, Vincent JL. Report from the meeting: Gastrointestinal Tonometry: State of the Art. 22nd–23rd May 1998, London, UK. Intensive Care Med 2000; 26: 613–22[CrossRef][Medline]

9 Mets B. Anesthesia for left ventricular assist device placement. J Cardiothorac Vasc Anesth 2000; 14: 316–26[ISI][Medline]