Fetal thrombotic vasculopathy in the placenta: a thrombophilic connection between pregnancy complications and neonatal thrombosis?

OBJECTIVE: Fetal thrombotic vasculopathy (FTV) has been related to pregnancy complications and neonatal thrombosis separately. We assessed whether a relationship existed in our population of women with neonates who were admitted to our Neonatal Intensive Care Unit (NICU). In addition, the presence of thrombophilic factors in children and parents was investigated. METHODS: Two groups were detected by a search of the departmental databases. Group A was a cohort of 5000 neonates admitted to our NICU (1992-2002). Infants who developed thrombotic complications were selected. Group B was a cohort of placentae from our institution (2000, n = 141). Those with a diagnosis of FTV were selected. Case-notes and laboratory results were obtained through the hospital information system. RESULTS: Of Group A, thrombosis was reported in 55 children. Of these, 20 matching placentae were available. Eight placentae showed FTV (40 per cent). Of the eight corresponding pregnancies, seven were complicated by pre-eclampsia and/or intra uterine growth restriction (IUGR). Of the 12 placentae without FTV, five of the pregnancies had pre-eclampsia and/or IUGR (odds ratio for relation FTV-Complications: 9.8, 95 per cent CI = 0.9-107). In Group B, nine placentae showed FTV (6.4 per cent). Of these nine, six of the pregnancies were complicated by pre-eclampsia and/or IUGR. None of the neonates developed thrombosis. CONCLUSION: Pre-eclampsia and/or IUGR as well as neonatal thrombosis are both associated with fetal thrombotic vasculopathy in the placenta. However, in our selected-tertiary centre-population, FTV did not predict neonatal thrombosis. The thrombophilic investigations of parents and children were incomplete. A standard approach for evaluating parents at risk for FTV and evaluating neonates at risk for thrombosis should be developed.

Referral and transportation for neonatal extracorporeal membrane oxygenation.

Data from 32 patients who were transported for neonatal extracorporeal membrane oxygenation (ECMO) over a 66-month period were reviewed. One ground ambulance transport had to be postponed because of poor weather conditions; the patient died. One patient was excluded for ECMO on arrival at the ECMO centre. Of the remaining 30 infants, 20 (67%) required ECMO treatment, of which four (20%) died. All 10 (33%) patients who were treated with conventional therapy survived. During transportation all children remained stable in terms of oxygenation. Early referral and transportation by an experienced and well-equipped transport team allows safe transport of these critically ill neonates.

Early activation of inflammation and clotting in the preterm lamb with neonatal RDS: comparison of conventional ventilation and high frequency oscillatory ventilation.

In neonatal respiratory distress syndrome activation of inflammation and clotting is demonstrated. High frequency oscillatory ventilation (HFOV) is considered to be less damaging to the human preterm lung, resulting in less activation of inflammation and clotting compared with conventional ventilation (CV). To assess the sequence of events of activation of inflammation and clotting and to compare the impact of HFOV to CV, we ventilated preterm lambs delivered by cesarean section at 132 d gestational age (term 145 d) for 8 h by CV (n = 10) or HFOV (n = 11). Fifteen minutes after birth and at 2-h intervals thereafter blood samples, from umbilical catheters, were analyzed for AP50 (complement activation), number of polymorphonuclear leukocytes, beta-glucuronidase, platelet function, activated partial thromboplastin time, thrombin time and thrombin inhibition, and bronchoalveolar lavage fluid was analyzed for elastase, thrombin and protein. We found complement activation, low number of polymorphonuclear leukocytes and high levels of beta-glucuronidase already at 15 min after birth. Within 2 to 4 h after birth platelet function deteriorated, activated partial thromboplastin time prolonged, and thrombin inhibition decreased. Activation of inflammation and clotting in the lungs was demonstrated by increased levels of elastase and thrombin in bronchoalveolar lavage fluid. In the HFOV group, AP50 remained significantly higher than in the CV group, reflecting less complement activation, and platelet function analysis remained significantly lower, reflecting better platelet function. We conclude that systemic activation of inflammation can be found in the ventilated preterm lamb with respiratory distress syndrome within 15 min after birth. Afterward, or due to activation of inflammation, clotting is activated. HFOV possibly attenuates activation of inflammation.

Recirculation in double lumen catheter veno-venous extracorporeal membrane oxygenation measured by an ultrasound dilution technique.

Recirculation is a limiting factor for oxygen delivery in double lumen catheter veno-venous extracorporeal membrane oxygenation (DLVV-ECMO). This study compares three different methods for the determination of the recirculation fraction during double lumen catheter veno-venous ECMO at ECMO flow rates of 150, 125, 100, 75, and 50 ml/kg.min in nine lambs: (1) an ultrasound dilution method, in which the change in ultrasound velocity in blood after injection of a saline bolus as a marker is used for determination of recirculation; (2) an SvO2 method using real mixed venous blood oxygen saturation, the gold standard, for determination of recirculation fraction; and (3) the CVL method, in which oxygen saturation of a blood sample of the inferior vena cava is considered to represent mixed venous oxygen saturation. In all methods, the recirculation fraction increased with increasing ECMO flow rate. The correlation coefficient between the ultrasound dilution method and the SvO2 method was 0.68 (p < 0.01); mean difference was -2.4% (p = 0.6). Correlation coefficient between the ultrasound dilution method and the CVL method was 0.48 (p < 0.01); mean difference was -18.1% (p < 0.01). The correlation coefficient between the SvO2 method and the CVL method was 0.51 (p < 0.01); mean difference was -15.7% (p < 0.01). The ultrasound dilution method is a useful method for measurement of the recirculation fraction in DLVV-ECMO and is easier to use than the other methods.

A multistate Kalman filter for neonatal clotting time prediction and early detection of coagulation disturbances.

The multistate Kalman filter was applied to develop a heparin dose proposal system and to detect coagulation disturbances during neonatal extracorporeal membrane oxygenation (ECMO). A system containing this filter was based on the activated clotting time (ACT) values and the heparin doses administered every hour during ECMO. If the ACT value can be predicted accurately from the previous heparin dose, a heparin dose proposal can be given to achieve or maintain the required ACT level. The analysis was done on 6,356 ACT level measurements in 44 ECMO neonates. The multistate Kalman filter technique showed an unbiased prediction of ACT, with a standard deviation of 23 seconds. Two out of three cases of disseminated intravascular coagulation (DIC) were detected. ACT values were predicted sufficiently accurately by the multistate Kalman filter technique to justify a prospective study on the performance of the heparin dose proposal system and its ability to detect DIC.

[Results of extracorporeal membrane oxygenation in 100 newborns with cardiorespiratory insufficiency]. / Resultaten van extracorporele membraanoxygenatie bij 100 pasgeborenen met cardiorespiratoire insufficiëntie.

OBJECTIVE: To describe the results of treatment with extracorporeal membrane oxygenation (ECMO) in newborns with severe cardiorespiratory insufficiency. DESIGN: Prospective, descriptive. METHODS: For all 100 newborns treated with ECMO in 1989-1997 in the Academic Hospital Nijmegen, department of Neonatology, the Netherlands, indications for treatment, complications during treatment and mortality within 6 weeks after cessation of ECMO were registered. RESULTS: The 100 children comprised 66 boys and 34 girls, with a mean age of 2 days (range: 1-15). Indications for ECMO treatment were: meconium aspiration syndrome: 39 with 37 survivors (95%), congenital diaphragmatic hernia: 31 with 23 survivors (74%), sepsis or pneumonia: 20 with 14 survivors (70%) and 'others' among which persistent pulmonary hypertension of the newborn: 10 with 8 survivors (80%). Eighteen children died (18%). Causes of death were rebound pulmonary hypertension (9 times), intracranial haemorrhage (4), multi-organ failure (3) and pulmonary problems (2). The most important complications during treatment were bleeding problems (29), clotting problems (20) and infections (11).

Surgical repair of congenital diaphragmatic hernia during extracorporeal membrane oxygenation: hemorrhagic complications and the effect of tranexamic acid.

Extracorporeal membrane oxygenation (ECMO) was incorporated in a strategy of delayed repair of congenital diaphragmatic hernia (CDH) and was used for preoperative stabilization in patients who were unresponsive to maximal conventional treatment. If ECMO was required for preoperative stabilization the diaphragmatic defect was repaired while the patient was on ECMO. In the early experience with this approach all patients suffered from bleeding complications. Therefore, we adopted the use of antifibrinolytic therapy with tranexamic acid (TEA) during and immediately after CDH repair on ECMO. The efficacy of TEA was studied in an unblinded study using historical controls by comparing the postoperative blood loss and the transfusion requirements of red blood cells (RBC) in patient groups treated without (n = 9) and with TEA (n = 10). Patients who received TEA had significantly less bleeding at the surgical site than patients not receiving TEA (57 v 390 mL, P = .005) and had significantly lower RBC transfusion requirements than patients not receiving TEA (1.13 v 2.95 mL/kg/h, P = .03). In the very first two patients of the TEA group we encountered fairly severe thrombotic complications. TEA may have contributed to those complications. Based on the authors' experience they conclude: (1) TEA is effective in reducing postoperative blood loss, hemorrhagic complications, and RBC transfusion requirements associated with CDH repair on ECMO. (2) TEA may be responsible for thrombotic complications. (3) The appropriate, empirically established, dosage and administration patterns of TEA for CDH repair during ECMO seem to be one bolus of 4 mg/kg TEA intravenously 30 minutes before the anticipated CDH repair and a continuous infusion of 1 mg/kg/h TEA during the 24 hours after CDH repair.

Simulation models in the planning of health care facilities: an application in the case of neonatal extracorporeal membrane oxygenation.

OBJECTIVES: To investigate whether modelling techniques can be used in the planning of health care facilities for patients requiring neonatal extracorporeal membrane oxygenation (ECMO). METHODS: In a micro-simulation model the number of patients that will have to be referred to facilities abroad is estimated for any number of neonatal ECMO patients presenting annually for treatment in The Netherlands, and any number of ECMO facilities. The inputs to the model consist of the number of ECMO facilities, the number of patients presenting annually, the duration of treatment and the date on which patients present for ECMO treatment. The model is estimated on data from The Netherlands for 1992, during which 29 patients were treated in three facilities. Several future scenarios are modelled, principally one in which a potential increase to 56 patients per year is foreseen. RESULTS: The model indicates that, if such an increase takes place, no additional ECMO facilities will be necessary in The Netherlands if between three and four referrals annually to centres outside the region (or abroad) are considered acceptable and feasible. In that situation, it is expected that on 22 occasions each year two patients will be treated simultaneously, for a total of 81 days. On ten occasions, all three facilities will be occupied at the same time, for 21 days in total. On 199 days, at least one of the facilities will be occupied. CONCLUSION: The current study shows that the acceptability and feasibility of patient referrals to ECMO centres abroad is an important issue which health care planners will have to consider. The study also shows that modelling techniques can provide information that is useful to policy-makers in the planning of health care facilities.

Follow-up in neonatal extracorporeal membrane oxygenation (ECMO).

In 34 survivors of the first 43 ECMO patients from our institution before discharge to another hospital or home an EEG, BAER, Head Ultrasonography, cerebral CT scan, Dubowitz score and ophthalmological inspection were performed. At one year of age Mental Developmental Index of the Bayley scales, Motor Quotient as well as pulmonary and neurological status were assessed. In 29 patients follow-up took place in our hospital. In 17 of them (59%) all tests before discharge were normal, 2 patients (7%) showed an abnormal BAER, an additional 5 patients (17%) had abnormal EEG and 2 patients (7%) had abnormal HUS in combination with abnormal cerebral CT scan. In 19 patients (33%) the Dubowitz score was abnormal at discharge. At one year of age neurological status was normal in 25 (86%) patients, respiratory status was normal in 22 (76%) and Mental Development Index was > 80 in 23 of the patients (79%). A significant correlation between Mental Development Index and Motor Quotient was found r = 0.50, p = 0.0065. It is concluded that more than one abnormal neurophysiological test before discharge may identify patients with additional risks for adverse outcome and that the respiratory status influenced psychomotor development at one year of age.

Improving survival for patients with high-risk congenital diaphragmatic hernia by using extracorporeal membrane oxygenation.

The benefit of extracorporeal membrane oxygenation (ECMO) in cases of high-risk congenital diaphragmatic hernia (CDH) was studied by comparing pre-ECMO (1987-1990) and post-ECMO (1991-1994) 3-month survival statistics. Fifty-five CDH patients who presented in respiratory distress within 6 hours after birth were referred--18 in the pre-ECMO era and 37 in the ECMO era. During the entire study period (December 1987 through July 1994) the patients were treated by the same protocol of preoperative stabilization and delayed surgery; the only difference was the addition of ECMO beginning in January 1991. The patients were stratified based on the response to conventional treatment: 1, no response (irretrievable); 2, stable; 3, unstable. The 3-month survival rate for the unstable neonates (who could not be stabilized by conventional therapy) improved from 0% (0 of 9) in the pre-ECMO era to 61% (11 of 18) in the ECMO era (P = .004). This highly significant difference shows that ECMO is a very valuable addition to the management of high-risk CDH patients whose conditions remain unstable despite maximal conventional therapy.

Disturbance of cerebral oxygenation and hemodynamics related to the opening of the bypass bridge during veno-arterial extracorporeal membrane oxygenation.

The objective of this study was to investigate changes of cerebral oxygenation and hemodynamics related to opening of the bypass bridge during veno-arterial extracorporeal membrane oxygenation (ECMO). Ten newborn infants and 12 piglets were studied during opening of the bridge for 10 and 1 s, respectively. Changes in cerebral concentration of oxyhemoglobin (cO2Hb), deoxyhemoglobin (cHHb), (oxidized-reduced) cytochrome aa3 (cCyt.aa3), and blood volume (CBV) were continuously measured by near infrared spectrophotometry. Heart rate, arterial O2 saturation (saO2), and mean arterial blood pressure (MABP) were measured simultaneously. In the piglets, central venous pressure (CVP), intracranial pressure (ICP), and left common carotid artery blood flow (CaBF) were also measured. Opening of the bridge for 10 s in the infants resulted in a significant decrease in MABP, saO2, and cO2Hb, whereas cHHb increased. CBV did not change significantly. In piglets biphasic changes were observed for MABP, CaBF, cO2Hb, and CBV, showing an initial decrease followed by a smaller increase. cHHb and CVP showed reverse biphasic changes. ICP increased but saO2 was unchanged. In all cases heart rate and cCyt.aa3 did not change significantly. Opening of the bridge for 1 s resulted in minor changes in only a few variables. In conclusion, opening of the bridge resulted in a decrease of CBV and cerebral O2 supply due to a decrease of cerebral blood flow, followed by a compensatory increase of cerebral O2 extraction and vasodilatation. The return of oxygenated blood after reclosing resulted in an increase of CBV with overcompensation of cerebral O2 supply.

Seldinger technique as an alternative approach for percutaneous insertion of hydrophilic polyurethane central venous catheters in newborns.

The use of hydrophilic central venous catheters, percutaneously inserted by means of the Seldinger technique, was evaluated in this prospective study. Between 1988 and 1991, 138 catheters were inserted in newborns who were admitted to our neonatal intensive care unit. An adequate position of the tip, evaluated radiographically, was achieved in 130 (94.2%) of these insertions. The side effects associated with these 130 catheters and the duration of their use were recorded. Results were compared with those of percutaneously inserted Silastic catheters described in the literature. The rate of adequate catheter placement seems comparable. Because of a high rate of minor mechanical complications, the mean catheter duration was rather short (8.3 days). However, the incidence of serious complications, especially infectious complications, was low.

Defibrination essential in the assay of ionized magnesium in mononuclear cells.

Intracellular free (ionized) magnesium concentration was measured in mononuclear cells isolated from healthy volunteers by use of dual wavelength fluorescence (indicator: mag-fura-2). We found a free Mg2+ concentration of 1.28 +/- 0.08 mmol/l in mononuclear cells isolated from heparinized blood. When we defibrinated blood samples prior to the isolation step we measured 0.78 +/- 0.05 mmol/l of free Mg2+ in these cells. We conclude that this difference is caused by the platelets present in the heparinized specimens.

Urokinase therapy in neonates with catheter related central venous thrombosis.

The results of fibrinolytic therapy with urokinase were evaluated in 26 neonates with catheter related central venous thrombosis. Complete thrombolysis could be achieved in 13 patients (50%), partial thrombolysis in 3 patients (12%). No effect was seen in 10 patients (38%). Therapy success was influenced by age, size and location of the thrombus. Coincidence of infection occurred in 16 patients (62%). Mild hemorrhagic complications were seen in 2 patients (8%), no other significant side effects were observed. Nine patients with residual thrombosis were treated with oral anticoagulants following urokinase resulting in resolution of the thrombus in 6 patients within 3 months (67%). The incidence of asymptomatic recurrent thrombosis was high (28%). Urokinase might be an effective and safe treatment for central venous thrombosis in neonates. Prophylactic antibiotic therapy during the infusion of urokinase and long-term treatment with oral anticoagulants after thrombosis are advisable. Early detection of thrombosis might enhance the success rate of fibrinolytic therapy. Therefore, we strongly recommend routine echocardiographic screening of central venous catheters.

Do we use the right entry criteria for extracorporeal membrane oxygenation in congenital diaphragmatic hernia?

In a retrospective review we analysed alveolar-arterial oxygen difference (AaDO2) as an entry criterion for extracorporeal membrane oxygenation (ECMO) in neonates with several forms of acute respiratory insufficiency. Although for meconium aspiration syndrome, respiratory distress syndrome, sepsis, and idiopathic pulmonary hypertension of the newborn we found values in accordance with the literature, patients with congenital diaphragmatic hernia (CDH) met 80% mortality criteria with significant lower AaDO2 values. Several patients died before ever reaching usual entry criteria for ECMO, because serious lung deterioration makes AaDO2 values unreliable. Awaiting classical ECMO entry criteria for patients with CDH may at least partially explain the lower survival rate for ECMO in CDH.

Magnesium metabolism in childhood.

Hypomagnesemia in childhood is relatively frequently noted in the neonatal period due to maternal causes, such as decreased intake due to vomiting, overuse of laxatives, and neonatal causes such as intrauterine growth retardation, birth asphyxia and exchange transfusion. A very rare cause of neonatal magnesium deficiency is called primary hypomagnesemia caused by impaired intestinal absorption of magnesium. Reference values of serum magnesium in cord blood are slightly lowered. Erythrocyte magnesium content is also lowered in cord blood and during the first month after birth. Mononuclear magnesium content shows no differences with age. Renal magnesium loss is diagnosed by the presence of hypomagnesemia with an inappropriately high 24-hour urinary magnesium excretion. In isolated familial hypomagnesemia an autosomal dominant as well as an autosomal recessive mode of inheritance was found. The renal magnesium threshold is lowered in both forms but the tubular maximum is only lowered in the dominant form. In familial hypomagnesemia-hypokalemia (Gitelman syndrome) the renal magnesium threshold is lowered but the tubular maximum is in the normal range. In this syndrome, with probably an autosomal recessive mode of inheritance, the renal defect might be located in the distal nephron after the medullary part of the ascending limb of the loop of Henle. The magnesium content of mononuclear cells and erythrocytes is in the normal and lower normal range, respectively. In the familial hypomagnesemia-hypercalciuria syndrome, hypomagnesemia is always combined with hyperuricemia and nephrocalcinosis. Myopia and horizontal nystagmus are often present.

Absent thumb, immune disorder, and congenital anemia presenting with hydrops fetalis.

A patient is described who presented with severe congenital anemia, hydrops fetalis, immune disorder, and absent thumbs. No toxic, infectious, or metabolic cause was found to explain these symptoms. Immunologic and cytogenetic studies excluded several syndromes that combine radial ray anomalies with hematological involvement. After careful study of the literature, it is concluded that the disorder described here represents a new syndrome that can be added to a growing list of hematological-radial syndromes.

31P nuclear magnetic resonance and zero-point titration compared for measuring free magnesium concentration in erythrocytes.

Intracellular ionized magnesium concentrations ([Mg2+]i) were measured in erythrocytes by 31P nuclear magnetic resonance (NMR) and zero-point titration in 14 controls and seven patients with renal magnesium loss. The mean intracellular ionized magnesium concentration in controls measured by 31P NMR was 0.20 (SD 0.03) mmol/L cell water, compared with 0.55 (SD 0.12) mmol/L cell water by zero-point titration. Total erythrocyte magnesium content measured with the lysate method was 0.63 mmol/L cell water higher than estimated by 31P NMR, probably because not all magnesium complexes are fully visible to the NMR technique. We found a positive correlation between plasma ultrafiltrable magnesium and [Mg2+]i irrespective of the [Mg2+]i assay used. [Mg2+]i measured with 31P NMR correlated modestly but significantly with [Mg2+]i determined by zero-point titration (r = 0.58, P less than 0.02). Washing erythrocytes before the zero-point titration decreased the ATP content and the cell water fraction, which led to overestimation of [Mg2+]i by zero-point titration. Although absolute values for [Mg2+]i differ with the assay used, both methods determined significantly lower values for [Mg2+]i in patients with isolated renal magnesium loss.