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Objective To evaluate the modeled predictive value of three current screening markers (pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (free β-hCG), and nuchal translucency (NT)) and four potential screening markers (a disintegrin and metalloprotease 12 (ADAM12), total hCG, placental protein 13 (PP13), and placental growth factor (PlGF)) for Down syndrome using different screening strategies. Methods All markers were measured in stored first-trimester serum of 151 Down syndrome cases and 847 controls. All marker levels were expressed as gestational age-specific multiples of the median (MoMs) and comparisons were made using the Mann-Whitney U-test. Detection rates (DRs) for fixed false-positive rates (FPRs) were modeled using different screening strategies. Results Significantly different median MoMs for Down syndrome cases compared to controls were found for PAPP-A (0.49 vs. 1.00; P < 0.0001), free β-hCG (1.70 vs. 1.01; P < 0.0001), ADAM12 (0.89 vs. 1.00; P < 0.0001), total hCG (1.28 vs. 1.00; P < 0.0001), PlGF (0.80 vs. 1.00; P < 0.0001) and NT (1.74 vs. 1.01; P < 0.0001). The lower PP13 MoM in Down syndrome cases (0.91 vs. 1.00) was not statistically significant (P = 0.061). Adding the four new markers to the current screening strategy (i.e. first-trimester combined test) led to an increase in DR from 77% to 80% at a 5% FPR. The modeled application of a two-sample screening strategy (with some markers assessed early and others later in the first trimester) increased the DR to 89%. In a two-step contingent screening model, using an intermediate risk range of 1 in 100 to 1 in 2000 at biochemical screening (using all markers), the overall DR was 77%, but it was predicted that only 33% of women would require referral for NT measurement. Conclusions First-trimester Down syndrome screening may be improved by adding new markers to the current screening test and by applying different screening strategies. The application of a two-sample screening model resulted in the highest predicted DR, but this should be confirmed in population-based prospective studies. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Please cite this paper as: Wortelboer E, Koster M, Cuckle H, Stoutenbeek P, Schielen P, Visser G. First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. BJOG 2010;117:1384–1389. Objective To investigate the predictive value of maternal serum pregnancy-associated plasma protein A (PAPP-A), free β subunit of human chorionic gonadotrophin (fβ-hCG), placental protein 13 (PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first-trimester identification of early-onset pre-eclampsia. Design Nested case–control study. Setting Routine first-trimester screening for trisomy 21 in the Netherlands. Population Eighty-eight women who developed pre-eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls. Methods PP13, PlGF and ADAM12 were measured in stored first-trimester serum, previously tested for PAPP-A and fβ-hCG. All marker levels were expressed in multiples of the gestation-specific normal median (MoMs). Model predicted detection rates for fixed false-positive rates were obtained for statistically significant markers alone and in combination. Main outcome measures Development of pre-eclampsia or HELLP syndrome. Results PP13 and PlGF were reduced in women with pre-eclampsia, with medians 0.68 MoM and 0.73 MoM respectively (P

Objectives To examine the predictive value of cervical length as measured by transvaginal sonography (TVS) in supine and upright maternal positions for the mode of delivery and induction-to-delivery interval after induction of labor at term, and to compare these measurements with the Bishop score and its predictive value. Methods TVS for cervical length measurement in the supine and upright positions and digital examination of the cervix were performed in 68 nulliparous and 34 parous women before induction of labor at term. In assessing the predictive value of the Bishop score and TVS parameters for a vaginal delivery after labor induction only nulliparous women were included in the analysis, since all the parous women delivered vaginally. Both nulliparous and parous women were included in the analysis of the induction-to-delivery interval. The method of labor induction, oxytocin or prostaglandin, was determined on the basis of the pre-induction Bishop score. Results Logistic regression analysis showed in nulliparous women that only the cervical length measured in the upright position was a significant predictor of the need for Cesarean section (odds ratio 1.14; 95% CI, 1.02–1.27). The areas under the receiver–operating characteristics curve in predicting the need for Cesarean section because of failure to progress were higher for the cervical length, both in supine and upright positions, than for the Bishop score (0.66, 0.68 and 0.46, respectively). Only the Bishop score correlated significantly with the induction-to-delivery interval in both nulliparous and parous women. However, this may have been due to a selection bias, as no significant correlation with Bishop score was found when the oxytocin and prostaglandin induction-to-delivery intervals were analyzed separately. Conclusion Our results suggest that maternal postural change might improve the accuracy of sonographically-measured cervical length for predicting a vaginal delivery after induction of labor at term. However, our results need to be confirmed in a larger and more homogeneous population. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

Objective. Our objective was to investigate the outcome of neonates with idiopathic polyhydramnios in the first year after birth. Methods. All patients diagnosed in the Erasmus Medical Centre Rotterdam and the University Medical Centre Utrecht between January 2000 and April 2005 with idiopathic polyhydramnios were studied. The outcome variables included mode of delivery, pre-term delivery, birth weight, macrosomia, large-for-gestational-age (weightp90), neonatal or infant mortality and infant morbidity at 1 year after delivery. These were related to antenatal findings, including the onset of polyhydramnios and ultrasonographic evidence of macrosomia (estimated fetal weightp90). Results. Polyhydramnios was diagnosed at a mean gestational age (s.d.) of 31.04.9 weeks. The mean gestational age at birth (s.d.) was 37.93.7 weeks. Macrosomia at birth was present in 25.3% (22/88). Sixty-three of 88 infants were in good health 1 year after birth; 20 infants had an abnormality and 5 children had died. Macrosomia and detection of polyhydramnios in the third trimester was associated significantly with a good outcome. Conclusion. In neonates with idiopathic polyhydramnios, abnormalities were detected during the first year of life in 28.4%. Detection of polyhydramnios in the second trimester and low or normal birth weight are risk factors for associated abnormalities.

Objective The aim of this study was to predict spontaneous onset of labor by serial transvaginal ultrasound measurement of cervical length (CL) in a homogeneous population of nulliparous women at term. Methods 162 nulliparous women with singleton fetuses in cephalic presentation were examined at weekly intervals from 36 weeks' gestation to delivery. CL was measured by transvaginal ultrasound in the supine and upright positions. Results There was a significant decrease in CL in the last 12 days prior to delivery. However, this decrease was small with substantial variation between individuals. Women with spontaneous onset of labor could be divided into three different groups: those with unchanged CL before delivery; those with a fall in CL in the last 2 weeks prior to delivery; and those with a gradual change in CL starting before the last 2 weeks prior to delivery. A single CL measurement below 30 mm between 37 and 38 weeks of gestation predicted spontaneous onset of labor before 41 weeks' gestation with a sensitivity of 46%, specificity of 78%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 40% in the supine position; and sensitivity of 53%, specificity of 72%, PPV of 81%, NPV of 40% in the upright position. Conclusion Between 37 and 38 weeks' gestation, spontaneous onset of labor before 41 weeks can be predicted by a CL measurement, but with low sensitivity and NPV. Inter-individual variations in CL and in CL changes are large, which hampers the value of single and repeated CL measurements for the prediction of spontaneous onset of labor at term. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives To determine whether estimation of gestational age (GA) in the context of first-trimester Down syndrome screening is standardized in the Netherlands. Methods This was a retrospective study, carried out between January 2005 and December 2006, of women who underwent first-trimester Down syndrome screening (n = 40 730) based on GA, maternal serum analysis and nuchal translucency (NT) measurement. Date of the last menstrual period (LMP), dating scan information including measurement of crown–rump length (CRL), NT thickness and name of the sonographer were recorded for all pregnancies. The accuracy of estimation of GA was evaluated by comparing the GA based on the LMP with that estimated from the CRL, using relevant subsets of the database. A survey of 104 sonographers was performed to further investigate the findings of the preceding analysis. Results In 44% of all first-trimester combined tests the estimation of GA was based on the dating scan; the method of determination of GA was unknown in 23%. In 15% of all cases a dating scan was recorded but was not used to provide the estimation of GA at blood sampling. Detailed analysis showed that a consistent methodology for the estimation of GA from CRL was not maintained within hospitals and obstetric practices. For a single CRL, the reported GA differed by up to 10 days. Finally, it was demonstrated that individual sonographers reported different GAs for a given CRL. Conclusions Currently, estimation of GA in the first trimester in the Netherlands is not standardized. To improve the performance of prenatal screening for Down syndrome, estimation of GA should be based on ultrasound examination, with one nationally accepted CRL curve. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

In the 36th week of gestation a large aortico-right ventricular tunnel with an otherwise structurally normal heart was diagnosed by fetal echocardiography. This report describes for the first time the impact of the timely prenatal diagnosis of an aortico-right ventricular tunnel followed by successful management in early infancy.

Evaluation of selective decontamination of the digestive tract (SDD) on late mortality in ventilated trauma patients in an intensive care unit (ICU).A multicenter, randomized controlled trial was undertaken in 401 trauma patients with Hospital Trauma Index-Injury Severity Score of 16 or higher. Patients were randomized to control (n=200) or SDD (n=201), using polymyxin E, tobramycin, and amphotericin B in throat and gut throughout ICU treatment combined with cefotaxime for 4 days. Primary endpoint was late mortality excluding early death from hemorrhage or craniocerebral injury. Secondary endpoints were infection and organ dysfunction.Mortality was 20.9% with SDD and 22.0% in controls. Overall late mortality was 15.3% (57/372) as 29 patients died from cerebral injury, 16 SDD and 13 control. The odds ratio (95% confidence intervals) of late mortality for SDD relative to control was 0.75 (0.40-1.37), corresponding to estimates of 13.4% SDD and 17.2% control. The overall infection rate was reduced in the test group (48.8% vs. 61.0%). SDD reduced lower airway infections (30.9% vs. 50.0%) and bloodstream infections due to aerobic Gram-negative bacilli (2.5% vs. 7.5%). No difference in organ dysfunction was found.This study demonstrates that SDD significantly reduces infection in multiple trauma, although this RCT in 401 patients was underpowered to detect a mortality benefit.

Objectives To determine the incidence and type of associated urogenital anomalies in children with a unilateral multicystic kidney and to assess in children with nephrectomy the additional diagnostic value of cystoscopy and, in girls, of colposcopy. Methods This was a follow-up study of 100 fetuses with antenatally detected unilateral multicystic kidneys. After ultrasound confirmation of the diagnosis within a few days after birth voiding cystourethrography and isotope scan were performed in 83 of the surviving children to exclude vesicoureteral reflux and to establish renal function. Eighty-one children underwent nephrectomy and, prior to surgery, all underwent cystoscopy and girls also underwent colposcopy. Results Seventy-five children had one or more additional urogenital anomalies: 39 had anomalies of the contralateral kidney, 40 had anomalies of the ipsilateral kidney and 30 had one or more anomalies of the lower urogenital tract. With cystoscopy 54 anomalies of the genitourinary tract were detected in 48 children and with colposcopy three anomalies were detected in 35 girls. Eighty-one children had a nephrectomy or heminephrectomy and 33 of them needed other urological intervention. Thirteen fetuses died (mostly from agenesis of the contralateral kidney) and six infants had no surgery at all. Conclusion Children with a unilateral multicystic kidney are at considerable risk of having other urogenital anomalies. When cystoscopy and colposcopy are added to routine investigations the rate of detection of anomalies is 75%, twice that reported in the literature. Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd.

The presence of maternal autoantibodies to SS-A/Ro and/or SS-B/La is associated with the development of fetal heart block. There are data suggesting that maternal treatment with steroids might reverse heart block. We report on a pregnancy in a mother with secondary Sjogren syndrome and systemic lupus erythematosus with presence of autoantibodies to SS-A/Ro and SS-B/La, which was complicated by the development of incomplete fetal heart block. Oral dexamethasone treatment could not prevent progression to complete heart block and was associated with a number of complications.A review of the literature revealed 19 studies (including ours) in which 93 cases of fetal heart block were treated with maternal steroid therapy. Complete heart block proved irreversible in all cases; and of 13 fetuses with incomplete heart block which received maternal steroid therapy, three had a reduction in their degree of block and one reverted to sinus rhythm. Maternal steroid therapy, initiated early in pregnancy and potentially preventing the onset of heart block, did not decrease the incidence of heart block in nine studies with 43 cases. Furthermore, the literature review revealed numerous serious side effects of maternal steroid administration during pregnancy. Data on these potential side effects are lacking in the 28 studies discussed in this review. Maternal dexamethasone therapy to prevent or treat fetal heart block remains, in our opinion, a questionable intervention and can as yet not be recommended in the clinical situation.

Background and methods: In six hydrocephalic foetuses (gestational age 29–38 wk), proton MR spectroscopy (1H-MRS) was performed in the basal ganglia for detection of lactate in vivo. Results: Lactate was present in two foetal brains, absent in two and not detectable because of movement in two. Conclusion: With adequate immobilization of the foetus, 1H-MRS can be used for detection of foetal brain lactate.

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) are the second and third most common autosomal trisomies after Down syndrome (trisomy 21). Most infants with a trisomy 18 or 13 die in utero and the others within the first year of life. Especially, in case of trisomy 13, there is an increased risk of severe and early onset pre-eclampsia (Boyd et al., 1987). To enable an early termination of trisomy 18 and 13 pregnancies, and to avoid maternal complications, screening for trisomy 18 and 13 seems a sensible option, especially since modelling has shown that current first trimester screening can detect both chromosomal anomalies with a high detection rate (DR) and low false positive rate (FPR) (Tul et al., 1999; Spencer et al., 2000). From January 2007 a governmentally approved national screening programme for Down syndrome has been implemented in the Netherlands, using the first trimester combined test [pregnancy-associated plasma protein A (PAPP-A), the free beta subunit of human choriongonadotrophin (fβ-hCG) and nuchal translucency (NT)]. The government license for this screening programme is strictly confined to screening for trisomy 21. Under the current license, it is not allowed to report on the risks for trisomy 18 and 13. However, since an increasing number of health care providers know the potential role of serum screening for trisomy 18 and 13, including some who already counsel their patient regarding these anomalies and since these trisomies are associated with early maternal complications it was recently decided to file a request to extend the government license to Edwards and Patau’s syndrome. This request is currently under review. The aim of this article is to predict the consequences for the Dutch screening programme in terms of DR and FPR if trisomy 18 and 13 screening is introduced, using an accepted algorithm and retrospective data of the Dutch programme.

OBJECTIVES The aim of this retrospective study was to evaluate perinatal atrial flutter (AF) and the efficacy of maternally administered antiarrhythmic agents, postpartum management and outcome. BACKGROUND Perinatal AF is a potentially lethal arrhythmia, and management of this disorder is difficult and controversial. METHODS Forty-five patients with documented AF were studied retrospectively. RESULTS Atrial flutter was diagnosed prenatally in 44 fetuses and immediately postnatally in 1 neonate. Fetal hydrops was seen in 20 patients; 17 received maternal therapy, 2 were delivered and 1 was not treated because it had a severe nontreatable cardiac malformation. In the nonhydropic group of 24 patients, 18 were treated and the remaining 6 were delivered immediately. In the hydropic group, 10 received single-drug therapy (digoxin or sotalol) and 7 received multidrug therapy. In the nonhydropic group, 13 received a single drug (digoxin or sotalol) and 5 received multiple drugs. One patient with rapid 1:1 atrioventricular conduction (heart rate 480 beats/min) died in utero and another died due to a combination of severe hydrops because of the AF, sotalol medication, stenosis of the venous duct and hypoplastic placenta. Of the 43 live-born infants, 12 were in AF at birth. Electrical cardioversion was successful in eight of nine patients. No recurrences in AF have occurred beyond the neonatal period. Four patients with fetal flutter and hydrops showed significant neurological pathology immediately after birth. CONCLUSIONS Fetal AF is a serious and threatening rhythm disorder; particularly when it causes hydrops, it may be associated with fetal death or neurological damage. Treatment is required and primarily aimed at reaching an adequate ventricular rate and preferably conversion to sinus rhythm. Digoxin failed in prevention of recurrence at time of delivery in a quarter of our patients, whereas with sotalol no recurrence of AF has been reported, suggesting that class III agents may be the future therapy. Once fetuses with AF survive without neurological pathology, their future is good and prophylaxis beyond the neonatal period is unnecessary.

Background: Food in the intestine drives the enterohepatic circulation of bile components. Objective: We investigated whether parenteral or enteral delivery of nutrients alters serum and biliary lipids in critically ill patients. Design: Eight intensive care unit (ICU) patients who had received ≥5 d of total parenteral nutrition (TPN) were compared with 8 ICU patients who had fasted for ≥5 d. Both groups were studied before and after 5 d of enteral nutrition (EN). Each patient served as his or her own control. Duodenal bile was analyzed for biliary lipid content and serum lipids were determined simultaneously. Duodenal bile samples from 18 healthy persons served as controls. Results: Bile salt concentrations in all ICU patients were 17% of control values before EN (P < 0.005) and 34% of control values after 5 d of EN (P < 0.005). Phospholipid concentrations were 12% of control before EN (P < 0.0005) but increased almost 4-fold after EN (P < 0.0005). Biliary cholesterol concentrations were 20% of control values before EN (P < 0.001) and did not improve afterward. No difference in bile composition was observed between fasted ICU patients and those who received TPN. The inverse correlation between the severity of illness and biliary lipid concentrations observed before EN disappeared with enteric stimulation. The low serum concentrations of HDL cholesterol and apolipoprotein A-I increased significantly with EN in all ICU patients. Conclusion: Lack of EN during critical illness was associated with profound decrements in biliary lipid concentrations that normalized partially after 5 d of EN. We hypothesize that loss of enteric stimulation in ICU patients impairs hepatic lipid metabolism.

Background To compare continuous cardiac output obtained by simulation of an aortic input impedance model to bolus injection thermodilution (TDCO) in critically ill patients with septic shock. Methods In an open study, mechanically ventilated patients with septic shock were monitored for 1 (32 patients), 2 (15 patients), or 3 (5 patients) days. The hemodynamic state was altered by varying the dosages of dopamine, norepinephrine, or dobutamine. TDCO was estimated 189 times as the series average of four automated phase-controlled injections of iced 5% glucose, spread equally over the ventilatory cycle. Continuous model-simulated cardiac output (MCO) was computed from radial or femoral artery pressure. On each day, the first TDCO value was used to calibrate the model. Results TDCO ranged from 4.1 to 18.2 l/min. The bias (mean difference between MCO and TDCO) on the first day before calibration was -1.92 +/- 2.3 l/min (mean +/- SD; n = 32; 95% limits of agreement, -6.5 to 2.6 l/min). The bias increased at higher levels of cardiac output (P < 0.05). In 15 patients studied on two consecutive days, the precalibration ratio TDCO:MCO on day 1 was 1.39 +/- 0.28 (mean +/- SD) and did not change on day 2 (1.39 +/- 0.34). After calibration, the bias was -0.1 +/- 0.8 l/min with 82% of the comparisons (n = 112) < 1 l/min and 58% (n = 79) < 0.5 l/min, and independent of the level of cardiac output. Conclusions In mechanically ventilated patients with septic shock, changes in bolus TDCO are reflected by calibrated MCO over a range of cardiac output values. A single calibration of the model appears sufficient to monitor continuous cardiac output over a 2-day period with a bias of -0.1 +/- 0.8 l/min.

Background Fetal tachyarrhythmia is a well-documented entity which, in the absence of pharmacological intervention, may lead to congestive heart failure, fetal hydrops and eventually fetal demise. The success rate of the implemented treatment is generally measured by survival and achievement of control of the arrhythmia. We report on the occurrence of associated cerebral damage in three patients with fetal tachycardia. Methods We describe three patients with a history of fetal supraventricular tachyarrhythmia who developed cerebral complications in utero. Results Two patients had cerebral hypoxic–ischemic lesions and one had hemorrhagic lesions present at birth. They had developed severe congestive heart failure and fetal hydrops secondary to fetal tachyarrhythmia, and there were no other obvious causes for the cerebral pathology. Two of these patients were referred to us antenatally. Therapy was instituted and resulted in control of the tachycardia and resolution of hydrops. The third patient was referred to our clinic shortly after birth because of severe circulatory problems secondary to fetal tachyarrhythmia. Conclusion From these observations, we believe that a fetus with tachyarrhythmia and subsequent hydrops is at increased risk for the development of cerebral complications, due to the circulatory disturbances and sudden changes in heart rate which may lead to fluctuations in cerebral perfusion. This would imply that it is of the utmost importance to aim at immediate and complete control of the heart rate in the treatment of fetal tachyarrhythmia.

SummaryThe aim of this study was to investigate the effects of a gelatin-based plasma expander on blood coagulation and haemostasis in human subjects.Six healthy men were studied in a randomised, controlled cross-over study to investigate the effects of a 60 min intravenous infusion of either 1 l gelatin-based plasma substitute (Gelofusine) or 0.9% NaCl (control). The infusion of gelatin resulted in a 1.7 fold increase in bleeding time at 60 min and a 1.4 fold increase at 120 min, while saline had no effect (p Our results demonstrated that the administration of a gelatin-based plasma substitute results in a significant impairment of primary haemostasis and thrombin generation. The defect in primary haemostasis appears to be related to a gelatin-induced reduction in von Willebrand factor, whereas the decreased thrombin generation may be due to the dilution of coagulation factors induced by Gelofusine.

Summary Background Studies to assess the prognostic value of early neurological and neurophysiological findings in patients with anoxic-ischaemic coma have not led to precise, generally accepted, prognostic rules. We did a systematic review of the relevant literature to assess whether such rules could be derived from the combined results of these studies. Methods From Medline and Embase databases we selected studies concerning patients older than 10 years with anoxicischaemic coma in which findings from early neurological examination, electroencephalogram (EEG), or somatosensory evoked potentials (SSEP) were related to poor outcome—defined as death or survival in a vegetative state. We selected variables with a specificity of 100% for poor outcome in all studies, and expressed the overall prognostic accuracy of these variables as pooled positive-likelihood ratios and as 95% CIs of the pooled false-positive test rates. Findings In 33 studies, 14 prognostic variables were studied, three of which had a specificity of 100%: absence of pupillary light reflexes on day 3 (pooled positive-likelihood ratio 10·5 [95% CI 2·1–52·4]; 95% CI pooled false-positive test rate 0–11·9%); absent motor response to pain on day 3 (16·8 [3·4–84·1]; 0–6·7%); and bilateral absence of early cortical SSEP within the first week (12·0 [5·3–27·6]; 0–2·0%). EEG recordings with an isoelectric or burstsuppression pattern had a specificity of 100% in five of six relevant studies (pooled positive-likelihood ratio 9·0 [2·5–33·1]; 95%CI pooled false-positive test rate 0·2–5·9%). These characteristics were present in 19%, 31%, 33%, and 33% of pooled patient populations, respectively. For the 11 SSEP studies, results did not significantly differ between studies in which the treating physicians were or were not masked from the test result, prospective and retrospective studies, studies with short and long follow-up periods, and studies with high or low overall poor outcome. Interpretation SSEP has the smallest CI of its pooled positive-likelihood ratio and its pooled false-positive test rate. Because evoked potentials are also the least susceptible to metabolic changes and drugs, recording of SSEP is the most useful method to predict poor outcome.

Background A body of evidence exists for the occurrence of bacterial translocation and its relationship to multiple organ failure (MOF). Methods Relevant articles on bacterial translocation (the phenomenon defined as the passage of microbes and endotoxin across the intestinal barrier) in patients prone to develop MOF and in representative animal studies were selected. To interpret and evaluate the evidence for bacterial translocation in current literature, the endpoints generally used are discussed. Results Fractional data from individual manuscripts were tabulated and assessed for statistical significance with X 2 analysis. Various clinically relevant stimuli, postulated as important causative factors for the development of MOF, appeared to be interrelated and related to bacterial translocation itself. Conclusions Convincing evidence exists that bacterial translocation can occur in humans during various disease processes. However, it remains to be determined whether a causal relationship between bacterial translocation and MOF exists. MOF is probably multifactorial and not uniform in origin; when evaluating translocation as a causative factor in the absence of an infective focus, the type of initiating event and the period of time after which MOF develops should be taken into account. The origin of early MOF is probably a non-bacterial, extensive, inflammatory response resulting in massive generalized endothelial cell activation. Late MOF may be caused primarily by bacterial translocation inducing an imbalance between proinflammatory and anti-inflammatory cytokines.

Aerobic Gram-negative bacilli (AGNB) carried in the gut by healthy individuals generate 1 mg of 'physiological' endotoxin per g of faeces. Successful eradication of AGNB from the gut would be expected to lead to a lowering of the intestinal endotoxin pool. This prompted us to evaluate the reduction of intestinal endotoxin in 6 healthy volunteers who each received 3 different oral antibiotic regimens. Regimen 1 was polymyxin E (600 mg/day), regimen 2 polymyxin E (400 mg/day) combined with tobramycin (320 mg/day) and regimen 3 pefloxacin (800 mg/day). Each regimen was separated by an antibiotic free period of 3 months. A faecal sample (minimally 2 g) was obtained from each volunteer, before treatment began and afterwards 3 times a week on alternating days (Monday, Wednesday, Friday) for 3 weeks. Each volunteer produced 30 samples, 10 each per oral antibiotic. The samples were serially diluted in nutrient broth for the colony count of AGNB, whilst endotoxin was measured using the classical Limulus amoebocyte lysate micro-assay. The base-line value of faecal AGNB was 10 3-4 colony forming units/g of faeces. All samples obtained on day 3 following antibiotic intake were negative for AGNB, and remained negative during antibiotic intake. The AGNB free carrier state was associated with a reduction in gut endotoxin. The reduction was approximately 10 ng (1 log) for polymyxin E and pefloxacin, whilst the combination of polymyxin/tobramycin significantly reduced the intestinal endotoxin concentrations from 1 mg to 100 ng in the gut; a reduction of 104. Although AGNB were killed by the three regimens, the 'free' endotoxin left in the gut was effectively neutralised by the combination polymyxin/tobramycin only. From a clinical point of view, gut-derived endotoxaemia may play a role in the systemic inflammatory response syndrome and hence the outcome, in critically ill intensive care patients. This study supports other work which indicates that mortality is significantly reduced in only those intensive care patients who received oral polymyxin/tobramycin.