A descriptive study of the variation in baseline levels of antiendotoxin core antibodies between US and UK populations.

Low levels of naturally occurring antibodies to the core section of endotoxin (EndoCAb) have been shown to be predictors of poor outcome following major surgery. We performed a retrospective study comparing pre-operative levels in US surgical patients, UK surgical patients and healthy volunteers. Both IgM and IgG EndoCAb levels were higher in the US surgical patients when compared with the other groups (approximately twice as high in the case of IgG EndoCAb). This may reflect genetic or environmental variability between the patient groups, differences in the disease processes, the disparity in the delivery of health care between the two countries or degradation of the samples in transfer.

The experience of the intensive care unit in a British Army field hospital during the 2003 Gulf conflict.

Over the last few years the Surgeon General's Department has overseen a major update in equipment scales for medical units in the field; anaesthesia and intensive care. This is to meet the aspiration of the Defence Chiefs, that injured servicemen on active service should receive the same standard of care as available in the United Kingdom. This paper discusses the experiences of the Intensive Care Unit operating within a Field Hospital both during the initial war fighting phase and subsequent peace keeping phase of the 2003 Gulf conflict (OP TELIC). Observations are made on patient activity, treatment strategy, and equipment adequacy.

Update on antiendotoxin therapies.

Endotoxin has been implicated in the processes that can lead to organ failure and death after surgery and critical illness. While there are no currently available commercial therapies directed against endotoxin, many have been tried or are in an experimental stage. In this article we outline past, present and future approaches to anti-endotoxin therapy.

The role of the gut in major surgical postoperative morbidity.

Gut mucosal hypoperfusion has been termed the motor of multiple organ failure. While a large proportion of high-risk surgery proceeds unremarkably, the insult to the inflammatory system during perioperative periods of regional hypoperfusion may manifest themselves over the subsequent few days, leading to microvascular thrombi, organ dysfunction, and failure. Several approaches have been made to prevent this, including systemic optimization of the cardiovascular system and specific targeting of the splanchnic circulation with monitoring techniques such as tonometry or metabolic markers of hepatic function to guide fluid and drug therapies. It is believed that in a proportion of patients such methods are not likely to suffice and gut mucosal hypoperfusion is probable. If these patients can be identified preoperatively, then recently developed techniques used prophylactically such as immunonutrition, passive and active immunization, specific antimediator agents, or nonspecific anti-inflammatory agents may help minimize the number of patients progressing to multiple organ dysfunction and failure. Techniques that may help us identify at-risk patients may include in-depth cardiovascular assessment, possibly with echocardiography or a noninvasive cardiac output monitor such as the suprasternal adaptation of the ODM esophageal Doppler. The measurement of baseline endotoxin immune status (EndoCAb) may select those patients in advance who are most at-risk from gut mucosal hypoperfusion, thus allowing a more rational use of tonometry. Conventional risk scoring systems used in conjunction with knowledge of the type of surgery to be undertaken and whether large fluid shifts are likely along with the less conventional techniques discussed above may enable perioperative therapy to be closer to optimal.

Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery.

STUDY OBJECTIVE: Endotoxin is a powerful trigger of systemic inflammation. Since cardiac surgery exposes patients to endotoxemia, this study was set up to define the relationship between preoperative endogenous endotoxin immune status, gut perfusion, and outcome following cardiac valve replacement surgery. DESIGN: Observational study. SETTING: University hospital. PATIENTS: Fifty-nine consecutive patients undergoing cardiac valve replacement. MEASUREMENTS AND MAIN RESULTS: Blood was assayed for IgG and IgM endotoxin core antibody (EndoCAb) levels preoperatively, immediately postoperatively, and at 4 h and 24 h postoperatively. Intraoperative gut mucosal perfusion was assessed using gastric tonometry. Complications were assessed for groups above and below the median EndoCAb value of a healthy population (100 median units micro/mL). Of the 59 patients, 12 developed at least one of a set of predefined complications. Of these 12, all had preoperative levels of IgM EndoCAb below 100 MU/mL (p<0.025). Eleven had IgG EndoCAb levels below 100 MU/mL (0.05

Comparison of commonly used clinical indicators of hypovolaemia with gastrointestinal tonometry.

OBJECTIVE: The gastrointestinal tonometer, which allows measurement of gastrointestinal mucosal CO2 and subsequent derivation of gut intramucosal pH (pHi), has been demonstrated to be a sensitive predictor of outcome following major surgery. Current theory suggests that the origin of the low pH may be hypovolaemia. This study was designed to compare the temporal sequence of changes in tonometric readings with invasive blood pressure, stroke volume, heart rate, lactate and arterial blood gas measurements during progressive haemorrhage. DESIGN: Observational healthy volunteer study. SETTING: Intensive care unit at University College London Hospitals. SUBJECTS: Six healthy, medically qualified volunteers. INTERVENTIONS: After obtaining baseline measurements, the subjects were progressively bled 25% (range = 21-31%) of their blood volume over a period of 1 h in two approximately equal aliquots. Equilibration was allowed for 30 min following the bleed, after which further measurements were made and the blood was then retransfused over 30 min. MEASUREMENTS AND MAIN RESULTS: There was no consistent change in any of the haemodynamic variables other than gastric intramucosal CO2:arterial CO2 gap (PiCO2-PaCO2) after removal of the first aliquot of blood, although five of the six subjects also demonstrated a fall in pHi. After removal of the second aliquot of blood, PiCO2-PaCO2 gap and pHi continued to indicate a worsening gastric intramucosal acidosis; stroke volume, as measured by suprasternal Doppler, demonstrated a marked fall, while all other variables measured had not altered consistently or to such a degree as to elicit a clinical response or cause suspicion of a hypovolaemic state. On retransfusion, all variables returned towards baseline. CONCLUSIONS: This study demonstrates the value of tonometry as an early monitor of hypovolaemia and highlights the shortcomings of other more commonly measured clinical variables.

Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery.

OBJECTIVE: To test the hypothesis that low serum antiendotoxin core antibody (EndoCAb) level is an independent predictor of adverse outcome following cardiac surgery. DESIGN: Prospective, blinded, cohort study. SETTING: Tertiary care medical center. SUBJECTS: A total of 301 patients undergoing coronary artery bypass graft surgery and/or valvular heart surgery. DESIGN: Preoperative serum was assayed for IgM EndoCAb, IgG EndoCAb, total IgM, and total IgG levels. Known preoperative risk factors were assessed, and patients were assigned a risk score using a validated method. MAIN OUTCOME MEASURE: A major complication, defined as either in-hospital death or postoperative length of stay greater than 10 days. RESULTS: Overall, a major complication occurred in 34 patients (11.3%). Lower IgM EndoCAb level independently predicted (P=.002) increased risk of major complication over and above the effects of preoperative risk score (P=.02), total IgG level (P=.07), and all other known perioperative risk factors. In contrast, IgG Endo-CAb and total IgM concentrations did not predict outcome. No association existed between risk score and level of IgM EndoCAb. CONCLUSION: There is marked preoperative variability in humoral immunity against endotoxin core, which is not accounted for by differences in known preoperative risk factors. In this study, low levels of IgMEndoCAb were an important independent predictor of adverse postoperative outcome, which supports the theory that endotoxemia is a cause of postoperative morbidity.

Haemostatic changes in the pulmonary blood during cardiopulmonary bypass.

Pulmonary injury may result from the use of cardiopulmonary bypass (CPB). We investigated changes in the haemostatic system in the pulmonary vein during CPB compared with blood that circulated through the bypass circuit. Paired samples were taken from the pulmonary vein and central venous pressure (CVP) line during the peri-operative period from ten patients. Plasma levels of factor VII (P < 0.001), prekallikrein (P < 0.05), antithrombin III (P < 0.001) and heparin cofactor II (P < 0.005) were decreased in the pulmonary vein after 20 min of bypass compared with pre-operative levels. In the pulmonary vein there was a significant increase in neutrophil expressed CD11b (P < 0.001), neutrophil elastase: alpha 1-antitrypsin complexes (P < 0.001), endothelin-1(P < 0.001) and thrombin-antithrombin complexes (P < 0.001) by the end of bypass compared with pre-operative levels. There was no significant change in monocyte expressed CD11b, factor XII or C1-esterase inhibitor in the pulmonary vein for the study period. None of these variables were significantly different in the pulmonary vein compared with CVP line. In the pulmonary vein plasma levels of activated factor VII decreased following heparin administration (P < 0.001) in the majority of patients which was coincidental to an increase (P < 0.001) in tissue factor pathway inhibitor (TFPI). This increase in TFPI was significantly higher in the pulmonary vein compared with CVP line (P < 0.05) There was a decrease in neutrophil count by 20 min on CPB in both the pulmonary vein and CVP line (P < 0.001) and this did not return to pre-operative levels in the pulmonary vein. Soluble thrombomodulin levels decreased by 20 min on CPB in the CVP line (P < 0.05) but tended to increase in the pulmonary vein, although this was not statistically significant. In conclusion we found evidence of thrombin generation and possible endothelial damage together with increased neutrophil activation and adhesion molecule expression in the pulmonary vein during CPB which may play an important role in the development of post-CPB pulmonary injury.

Passive immunisation with IgG endotoxin core antibody hyperimmune fresh frozen plasma.

Postoperative complications have been associated with low pre-operative endotoxin core antibody (EndoCAb) status. Seventy-three patients scheduled to undergo elective cardiac surgery were screened for IgG EndoCAb levels 1 week prior to admission. Of these 73 patients, 39 had levels below the median of a healthy population (100 MU = median units/ml). Only 6 received an infusion of IgG EndoCAb hyperimmune fresh frozen plasma (FFP) due to surgical rescheduling or unavailability of compatible hyperimmune FFP. The 6 patients demonstrated significant elevation (p < 0.0001) of their IgG EndoCAb levels from a mean level of 43 MU/ml (range: 26-75) to a posttransfusion mean of 267 MU/ml (range: 227-300), which persisted until at least immediately prior to the operative period. We conclude that passive immunisation with EndoCAb hyperimmune FFP is possible prior to elective surgery and that the kinetic profile of such an administration will allow the FFP to be given the night prior to surgery and still maintain significantly elevated levels for surgery planned the following morning.

Physostigmine in recovery from anaesthesia.

Intravenous ketamine anaesthesia has been used by the British army in the field for many years. A recognised problem has been the unpredictable recovery profile this produces. We anaesthetised 28 ASA 1 patients using a standard British military technique. At termination of the anaesthetic, half of the patients were given a physostigmine/glycopyrronium mixture and half were given the equivalent volume of saline 0.9%. There was a significant difference between the two groups with regard to recovery times (p < 0.001). There was no significant difference with regard to other variables. In trauma anaesthesia the improved recovery profile from the use of physostigmine following ketamine anaesthesia may lead to earlier evacuation of the patient.

The role of endotoxin immunity, neutrophil degranulation and contact activation in the pathogenesis of post-operative organ dysfunction.

Gut mucosal hypoperfusion is associated with a poor outcome following major surgery but the pathogenetic mechanisms remain poorly understood. We have examined the relationship between gut mucosal hypoperfusion, endotoxin core antibodies (EndoCAb), neutrophil elastase alpha-1 antitrypsin complexes (NE) and components of the contact system during elective major surgery. Of the 26 patients studied 16 developed gut mucosal hypoperfusion (pHi < 7.32) by the end of surgery; of these four developed multiple organ failure (MOF) and three subsequently died. In this group there was a significant rise in NE (P < 0.005) and significant reductions in components of the contact system (factor XII, antithrombin III, prekallikrein and C1-inhibitor; P < 0.001) from immediately before surgery to 24 h later. Ten patients maintained gut mucosal perfusion (pHi > or = 7.32); none of these developed life threatening complications. In this group there was no significant increase in NE and, although there were significant reductions in some components of the contact system (P < 0.01), levels of C1-INH were not reduced. All patients demonstrated a significant reduction in both IgG and IgM EndoCAbs (P < or = 0.005) indicating exposure to endotoxin. However, the group that maintained gut mucosal perfusion had significantly higher IgG EndoCAb levels at baseline and 24 h (P < or = 0.005). These data suggest that all patients were exposed to endotoxin and that high levels of anti-endotoxin antibodies may contribute to the prevention of endotoxin-induced contact activation, neutrophil degranulation and gut mucosal hypoperfusion occurring during major surgery and thus reduce the likelihood of the development of post-operative MOF.