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Major orthopaedic surgery and post-discharge DVT
THE LANCET
COMMENTARY
Factors contributing to pathogenesis of IVH Variation in cerebral blood flow Disturbance of platelet-capillary function and coagulation Immaturity of vascular bed in the germinal matrix with deficient vascular support Ischaemic injury to the vessels leading to rupture after reperfusion Factors in handling of the baby (excessive handling, tracheal suctioning, rapid infusion of hypertonic solutions, exchange transfusions, and artificial ventilation leading to pneumothorax)
percentage (up to 40%) of premature babies born under 32 weeks of gestational age, sometimes without clinical signs. More recently a percentage of 15–20% has been reported by some neonatal units.1 Severe IVH/PVL has been reported to decline by 57% between 1988 and 1994.3 The pathogenesis is thought to be multifactorial (panel).
Interventions for prevention of IVH-PVH—for example, the use of phenobarbitone and vitamin E—have not been very successful. The only preventive measure to lower the incidence of IVH-PVH that increases survival intact is the use of steroids antenatally.4 A clinical trial of the routine use of early volume expansion with fresh frozen plasma (FFP) or gelatin soon after birth is reported in this issue of The Lancet. The trial is well designed and executed, especially in view of the fact that the primary trial outcome chosen was not ultrasound imaging but survival without severe disability, which needs long-term follow-up. The researchers conclude that there is little evidence to suggest that routine early administration of FFP or some other form of intravascular volume expansion to babies born more than 8 weeks early alters the risk of death or disability. The routine use of plasma expanders, as adopted in some parts of the UK, is not widespread practice. However, in Europe many neonatologists give plasma protein fraction or another plasma expander almost routinely when the baby’s blood pressure drops, to prevent ischaemic brain damage. Cardiac dysfunction is a commoner cause of a drop in blood pressure than is hypovolaemia. Measuring central venous pressure and echocardiography can distinguish between the two.5 The use of FFP has the disadvantages of being expensive and of the possibility of transfer of as yet unknown viruses. Apart from steroids given antenatally, early treatment with low doses of indomethacin or, even better, ibuprofen seems promising. The severe form of IVH (grade 4 IVH) was less likely among babies given indomethacin prophylactically at 6-12 h, compared with those given a placebo.6 However, follow-up at 3 years of age revealed no difference in the incidence of cerebral palsy between the two groups. Thus steroids given antenatally remains the best option for preventing PVH-IVH. The care of the premature baby before and during delivery and in the first few days after birth has improved considerably in the past 30 years. Technical advances, antenatal administration of steroids, and surfactantreplacement therapy have been very successful. However, simple measures that improve outcome, such as late
Vol 348 • July 27, 1996
clamping of the cord, seem to have been forgotten.7 Because neonatal intracranial bleeding and cerebral ischaemia are multifactorial in origin, efforts at prevention probably need to include several measures before and after birth. Rates of mortality and severe disability are especially high in premature babies born before 28 weeks of gestation. For them carefully planned research, such as the trial on FFP, in both obstetrics and neonatology is needed. An important incidental message for ethical decisionmaking, from the FFP study, is the remark in the discussion on the predictive value of cranial ultrasound imaging. Decisions to withhold or withdraw intensive care are commonly made on the basis of such predictions. In this study nearly half the children with an ultrasound finding considered serious enough to make long-term disability likely showed no signs of severe impairment later on. This finding makes prediction in individual cases tricky.
Janna G Koppe Department of Neonatology, Academisch Ziekenhuis, University of Amsterdam, 1105 AZ, Amsterdam, Netherlands 1
2
3
4
5
6
Eken P. Cerebral visual impairment in infants with haemorrhagicischaemic lesions of the neonatal brain. Thesis, University of Utrecht, 1996. De Vries LS, Dubowitz LMS, Dubowitz V, et al. Predictive value of cranial ultrasound in the newborn baby: a reappraisal. Lancet 1985; ii: 137–40. Oh W, Fanaroff AA, Verter J, et al. Neonatal mortality and morbidity in very low birth-weight (VLBW) infants: a seven year trend analysis of the Neonatal Network data. Pediatr Res 1996; 39: 235A. National Institutes of Health consensus development conference statement. Effects of corticosteroids for fetal maturation on prenatal outcomes. Am J Obstet Gynecol 1995; 173: 246–52. Gill AB, Weindling AM. Echocardiographic assessment of cardiac function in shocked very low birthweight infants. Arch Dis Child 1993; 68: 17–21. Ment LR, Oh W, Ehrnkranz RA, et al. Low dose indomethacin and
Major orthopaedic surgery and post-discharge DVT See page 224 In this week’s issue Planes et al report a single-centre, double-blind, randomised study designed to determine the risk of venous thromboembolism and the risk reduction by a lengthy period (3 weeks) of anticoagulant treatment after hospital discharge in patients who underwent total hipreplacement surgery. While in hospital all patients received prophylactic treatment with low-molecularweight heparin (LMWH), which is current practice in many orthopaedic surgery units. Shortly before discharge (13-15 days after surgery) they underwent bilateral ascending contrast venography, a measure designed specifically for this trial and not common practice. Patients with a normal venogram were then randomised either to continuing LMWH prophylaxis or to placebo for another 3 weeks as outpatients, followed by contrast venography again. Among the patients who underwent repeat venography (173 out of 179 patients) there was an overall incidence of 13% (23 out of 173 patients) venography-confirmed thrombosis. 6 of the 23 patients had received LMWH prophylaxis (7%) and 17 placebo (19%). Only about half the patients (10 out of 23 patients) with deep-vein thrombosis had symptoms or clinical signs of the complication. No deaths or episodes of symptomatic pulmonary embolism were observed during the study period. Post-discharge LMWH prophylaxis 209
THE LANCET
COMMENTARY was not associated with clinically relevant bleeding, and only one patient had moderate symptomless thrombocytopenia. What is the significance of these findings? First, the overall incidence of contrast-venography-confirmed thrombosis at 3 weeks post-discharge was surprisingly high—ie, 13% compared with 19% in placebo-treated patients—especially since only patients with a normal venogram before randomisation were included in this study. The incidence is even more surprising because of the strict eligibility criteria for this study. Patients were eligible only if they were fully ambulatory (able to walk without assistance other than crutches) and had no disorders known to be associated with an enhanced risk of venous thromboembolism (no history of deep-vein thrombosis or pulmonary embolism or the presence of active malignancy). Three of the patients who developed deep-vein thrombosis had had a history of malignancy, but that still leaves 20 patients without a reason for the complication. Hence, contrast venography—even under the very favourable technical circumstances pertaining in the study—cannot be excluded as being a contributory factor to the thrombosis. In a careful follow-up study1 in 41 consecutive patients with leg symptoms but without evidence of thrombosis on normal contrast venography, a subsequent 125I-fibrinogen leg scan revealed thrombosis, which was confirmed by repeat contrast venography in one patient. The frequency of venous thrombosis after venography with non-ionic low-osmolar contrast medium followed by flushing in that study was therefore 2%, with 95% confidence limits of 0 and 13%. Therefore a part of the 19% frequency of thrombosis in placebo-treated patients in the study by Planes et al may be related to the contrast-venography procedure. Second, prophylaxis against thrombosis with LMWH for 3 weeks resulted in an absolute risk reduction of thrombosis of 12·2% (7·1% vs 19·3% in patients receiving placebo). These observations support the antithrombotic efficacy of LMWH revealed by many studies in post-surgical patients at variable risk.2 However, this risk reduction was not associated with a reduced risk of proximal vein thrombosis (5·9% in the LMWH-treated patients vs 7·9% in the placebo-treated patients). Moreover, 6 out of 85 patients treated with LMWH had deep-vein thrombosis and 5 of those thromboses were proximally located. These findings imply that, even after treatment for 3 weeks after discharge, a subset of patient with proximal deep-vein thrombosis remains. In conclusion, this well-conducted study shows that among patients who have undergone total hipreplacement surgery, followed by venography before discharge, post-discharge deep-vein thrombosis as assessed by repeat venography is common, and LMWH is able to reduce the incidence of post-discharge distal thrombosis. The clinical implications are not immediately clear. Is the risk of post-discharge thrombosis also high when patients do not undergo pre-discharge venography? Is venography-confirmed distal thrombosis a clinically important entity? In follow-up studies examining clinical events the incidence of such events has been low.3,4 In the study by Planes, although a third of patients had leg symptoms, they were not subjected to diagnostic tests. Neither was there evidence that LMWH prophylaxis was 210
less likely to be associated with symptoms (14 in the LMWH vs 16 in the placebo group had clinical signs of DVT). There is a clear need for a more definitive randomised clinical trial, in which patients are randomised to shortterm (10 days, followed by placebo) and long-term (3 to 6 weeks active treatment) prophylaxis, with venography only at the end of the study, or for a very large clinical endpoint study with strict rules for outcome detection. Orthopaedic surgeons who prescribe short courses of prophylactic anticoagulants will not find enough evidence to extend this regimen because of the problem of generalisability of Planes and colleagues’ findings, and those who give longer courses (a strategy for which there is not much evidence but that is common practice) will not confidently stop doing so. In summary, the trial highlights the potential importance of post-discharge thrombosis, but will not change current practice.
Jan W ten Cate, Martin H Prins Departments of Vascular Medicine and Clinical Epidemiology— Biostatistics, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands 1
2
3
4
Lensing AWA, Prandoni P. Büller HR, Casare D, Cogo A, ten Cate JW. Lower extremity venography with iohexol: results and complications. Radiology 1990; 177: 503–05. Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecularweight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340: 152–56. Hoek JA, Nurmohamed MT, Hamelynck KJ, et al. Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid. Thromb Haemost 1992; 67: 28–32. Agnelli G, Ranucci V, Veschi F, Rinonapoli E, Lupatelli L, Nenci GG. Clinical outcome of orthopaedic patients with negative lower limb venography at discharge. Thromb Haemost 1995; 74: 1092–44.
New technology and recurrent varicose veins Recent reports of use of colour doppler duplex scanning in the preoperative assessment of varicose veins suggest that almost universal acceptance of this mode of investigation.1,2 This attitude raises two questions. Is the technique acceptable when compared with phlebography, a historical gold standard? And what do these investigations teach that allows us to modify our operations to reduce or prevent recurrence of varicose veins? Clinical examination, so important and so accurate in assessing limbs with arterial insufficiency, is notoriously inaccurate in determining saphenofemoral and saphenopopliteal incompetence.3 Such is also true for the detection of perforating veins.4 These points of venous dysfunction are the ones most associated with recurrent varices. Addition of the hand-held, continuous-wave doppler examination to the clinical assessment does improve the evaluation but the technique is flawed because of a high likelihood of false-positive findings.5 The colour-coded duplex ultrasound instrument, however, yields findings that correlate reasonably closely with those of phlebography.6 This fact and the invasive nature of phlebography, with its potential for reactions to the contrast medium, has led to a near-total acceptance of ultrasound as the single most important preoperative investigation. From these investigations there are at least three lessons that can be learnt to decrease the incidence of
Vol 348 • July 27, 1996
COMMENTARY
Factors contributing to pathogenesis of IVH Variation in cerebral blood flow Disturbance of platelet-capillary function and coagulation Immaturity of vascular bed in the germinal matrix with deficient vascular support Ischaemic injury to the vessels leading to rupture after reperfusion Factors in handling of the baby (excessive handling, tracheal suctioning, rapid infusion of hypertonic solutions, exchange transfusions, and artificial ventilation leading to pneumothorax)
percentage (up to 40%) of premature babies born under 32 weeks of gestational age, sometimes without clinical signs. More recently a percentage of 15–20% has been reported by some neonatal units.1 Severe IVH/PVL has been reported to decline by 57% between 1988 and 1994.3 The pathogenesis is thought to be multifactorial (panel).
Interventions for prevention of IVH-PVH—for example, the use of phenobarbitone and vitamin E—have not been very successful. The only preventive measure to lower the incidence of IVH-PVH that increases survival intact is the use of steroids antenatally.4 A clinical trial of the routine use of early volume expansion with fresh frozen plasma (FFP) or gelatin soon after birth is reported in this issue of The Lancet. The trial is well designed and executed, especially in view of the fact that the primary trial outcome chosen was not ultrasound imaging but survival without severe disability, which needs long-term follow-up. The researchers conclude that there is little evidence to suggest that routine early administration of FFP or some other form of intravascular volume expansion to babies born more than 8 weeks early alters the risk of death or disability. The routine use of plasma expanders, as adopted in some parts of the UK, is not widespread practice. However, in Europe many neonatologists give plasma protein fraction or another plasma expander almost routinely when the baby’s blood pressure drops, to prevent ischaemic brain damage. Cardiac dysfunction is a commoner cause of a drop in blood pressure than is hypovolaemia. Measuring central venous pressure and echocardiography can distinguish between the two.5 The use of FFP has the disadvantages of being expensive and of the possibility of transfer of as yet unknown viruses. Apart from steroids given antenatally, early treatment with low doses of indomethacin or, even better, ibuprofen seems promising. The severe form of IVH (grade 4 IVH) was less likely among babies given indomethacin prophylactically at 6-12 h, compared with those given a placebo.6 However, follow-up at 3 years of age revealed no difference in the incidence of cerebral palsy between the two groups. Thus steroids given antenatally remains the best option for preventing PVH-IVH. The care of the premature baby before and during delivery and in the first few days after birth has improved considerably in the past 30 years. Technical advances, antenatal administration of steroids, and surfactantreplacement therapy have been very successful. However, simple measures that improve outcome, such as late
Vol 348 • July 27, 1996
clamping of the cord, seem to have been forgotten.7 Because neonatal intracranial bleeding and cerebral ischaemia are multifactorial in origin, efforts at prevention probably need to include several measures before and after birth. Rates of mortality and severe disability are especially high in premature babies born before 28 weeks of gestation. For them carefully planned research, such as the trial on FFP, in both obstetrics and neonatology is needed. An important incidental message for ethical decisionmaking, from the FFP study, is the remark in the discussion on the predictive value of cranial ultrasound imaging. Decisions to withhold or withdraw intensive care are commonly made on the basis of such predictions. In this study nearly half the children with an ultrasound finding considered serious enough to make long-term disability likely showed no signs of severe impairment later on. This finding makes prediction in individual cases tricky.
Janna G Koppe Department of Neonatology, Academisch Ziekenhuis, University of Amsterdam, 1105 AZ, Amsterdam, Netherlands 1
2
3
4
5
6
Eken P. Cerebral visual impairment in infants with haemorrhagicischaemic lesions of the neonatal brain. Thesis, University of Utrecht, 1996. De Vries LS, Dubowitz LMS, Dubowitz V, et al. Predictive value of cranial ultrasound in the newborn baby: a reappraisal. Lancet 1985; ii: 137–40. Oh W, Fanaroff AA, Verter J, et al. Neonatal mortality and morbidity in very low birth-weight (VLBW) infants: a seven year trend analysis of the Neonatal Network data. Pediatr Res 1996; 39: 235A. National Institutes of Health consensus development conference statement. Effects of corticosteroids for fetal maturation on prenatal outcomes. Am J Obstet Gynecol 1995; 173: 246–52. Gill AB, Weindling AM. Echocardiographic assessment of cardiac function in shocked very low birthweight infants. Arch Dis Child 1993; 68: 17–21. Ment LR, Oh W, Ehrnkranz RA, et al. Low dose indomethacin and
Major orthopaedic surgery and post-discharge DVT See page 224 In this week’s issue Planes et al report a single-centre, double-blind, randomised study designed to determine the risk of venous thromboembolism and the risk reduction by a lengthy period (3 weeks) of anticoagulant treatment after hospital discharge in patients who underwent total hipreplacement surgery. While in hospital all patients received prophylactic treatment with low-molecularweight heparin (LMWH), which is current practice in many orthopaedic surgery units. Shortly before discharge (13-15 days after surgery) they underwent bilateral ascending contrast venography, a measure designed specifically for this trial and not common practice. Patients with a normal venogram were then randomised either to continuing LMWH prophylaxis or to placebo for another 3 weeks as outpatients, followed by contrast venography again. Among the patients who underwent repeat venography (173 out of 179 patients) there was an overall incidence of 13% (23 out of 173 patients) venography-confirmed thrombosis. 6 of the 23 patients had received LMWH prophylaxis (7%) and 17 placebo (19%). Only about half the patients (10 out of 23 patients) with deep-vein thrombosis had symptoms or clinical signs of the complication. No deaths or episodes of symptomatic pulmonary embolism were observed during the study period. Post-discharge LMWH prophylaxis 209
THE LANCET
COMMENTARY was not associated with clinically relevant bleeding, and only one patient had moderate symptomless thrombocytopenia. What is the significance of these findings? First, the overall incidence of contrast-venography-confirmed thrombosis at 3 weeks post-discharge was surprisingly high—ie, 13% compared with 19% in placebo-treated patients—especially since only patients with a normal venogram before randomisation were included in this study. The incidence is even more surprising because of the strict eligibility criteria for this study. Patients were eligible only if they were fully ambulatory (able to walk without assistance other than crutches) and had no disorders known to be associated with an enhanced risk of venous thromboembolism (no history of deep-vein thrombosis or pulmonary embolism or the presence of active malignancy). Three of the patients who developed deep-vein thrombosis had had a history of malignancy, but that still leaves 20 patients without a reason for the complication. Hence, contrast venography—even under the very favourable technical circumstances pertaining in the study—cannot be excluded as being a contributory factor to the thrombosis. In a careful follow-up study1 in 41 consecutive patients with leg symptoms but without evidence of thrombosis on normal contrast venography, a subsequent 125I-fibrinogen leg scan revealed thrombosis, which was confirmed by repeat contrast venography in one patient. The frequency of venous thrombosis after venography with non-ionic low-osmolar contrast medium followed by flushing in that study was therefore 2%, with 95% confidence limits of 0 and 13%. Therefore a part of the 19% frequency of thrombosis in placebo-treated patients in the study by Planes et al may be related to the contrast-venography procedure. Second, prophylaxis against thrombosis with LMWH for 3 weeks resulted in an absolute risk reduction of thrombosis of 12·2% (7·1% vs 19·3% in patients receiving placebo). These observations support the antithrombotic efficacy of LMWH revealed by many studies in post-surgical patients at variable risk.2 However, this risk reduction was not associated with a reduced risk of proximal vein thrombosis (5·9% in the LMWH-treated patients vs 7·9% in the placebo-treated patients). Moreover, 6 out of 85 patients treated with LMWH had deep-vein thrombosis and 5 of those thromboses were proximally located. These findings imply that, even after treatment for 3 weeks after discharge, a subset of patient with proximal deep-vein thrombosis remains. In conclusion, this well-conducted study shows that among patients who have undergone total hipreplacement surgery, followed by venography before discharge, post-discharge deep-vein thrombosis as assessed by repeat venography is common, and LMWH is able to reduce the incidence of post-discharge distal thrombosis. The clinical implications are not immediately clear. Is the risk of post-discharge thrombosis also high when patients do not undergo pre-discharge venography? Is venography-confirmed distal thrombosis a clinically important entity? In follow-up studies examining clinical events the incidence of such events has been low.3,4 In the study by Planes, although a third of patients had leg symptoms, they were not subjected to diagnostic tests. Neither was there evidence that LMWH prophylaxis was 210
less likely to be associated with symptoms (14 in the LMWH vs 16 in the placebo group had clinical signs of DVT). There is a clear need for a more definitive randomised clinical trial, in which patients are randomised to shortterm (10 days, followed by placebo) and long-term (3 to 6 weeks active treatment) prophylaxis, with venography only at the end of the study, or for a very large clinical endpoint study with strict rules for outcome detection. Orthopaedic surgeons who prescribe short courses of prophylactic anticoagulants will not find enough evidence to extend this regimen because of the problem of generalisability of Planes and colleagues’ findings, and those who give longer courses (a strategy for which there is not much evidence but that is common practice) will not confidently stop doing so. In summary, the trial highlights the potential importance of post-discharge thrombosis, but will not change current practice.
Jan W ten Cate, Martin H Prins Departments of Vascular Medicine and Clinical Epidemiology— Biostatistics, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands 1
2
3
4
Lensing AWA, Prandoni P. Büller HR, Casare D, Cogo A, ten Cate JW. Lower extremity venography with iohexol: results and complications. Radiology 1990; 177: 503–05. Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecularweight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992; 340: 152–56. Hoek JA, Nurmohamed MT, Hamelynck KJ, et al. Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid. Thromb Haemost 1992; 67: 28–32. Agnelli G, Ranucci V, Veschi F, Rinonapoli E, Lupatelli L, Nenci GG. Clinical outcome of orthopaedic patients with negative lower limb venography at discharge. Thromb Haemost 1995; 74: 1092–44.
New technology and recurrent varicose veins Recent reports of use of colour doppler duplex scanning in the preoperative assessment of varicose veins suggest that almost universal acceptance of this mode of investigation.1,2 This attitude raises two questions. Is the technique acceptable when compared with phlebography, a historical gold standard? And what do these investigations teach that allows us to modify our operations to reduce or prevent recurrence of varicose veins? Clinical examination, so important and so accurate in assessing limbs with arterial insufficiency, is notoriously inaccurate in determining saphenofemoral and saphenopopliteal incompetence.3 Such is also true for the detection of perforating veins.4 These points of venous dysfunction are the ones most associated with recurrent varices. Addition of the hand-held, continuous-wave doppler examination to the clinical assessment does improve the evaluation but the technique is flawed because of a high likelihood of false-positive findings.5 The colour-coded duplex ultrasound instrument, however, yields findings that correlate reasonably closely with those of phlebography.6 This fact and the invasive nature of phlebography, with its potential for reactions to the contrast medium, has led to a near-total acceptance of ultrasound as the single most important preoperative investigation. From these investigations there are at least three lessons that can be learnt to decrease the incidence of
Vol 348 • July 27, 1996