Anke H. Scultetus

Microthrombectomy reduces postsclerotherapy pigmentation: multicenter randomized trial

OBJECTIVE Postsclerotherapy pigmentation occurs in nearly 30% of patients. Hemosiderin, from degradation of the venous thrombus, is the possible cause. The hypothesis that early removal of the thrombus may eliminate or decrease the incidence of pigmentation has not been proved or documented. The objective of this study was to investigate the effects of early microthrombectomy on incidence of postsclerotherapy pigmentation. MATERIAL AND METHODS This multicenter, randomized, controlled study involved 101 patients with varicose veins (100 women, 1 man; mean age, 46 years [range, 25-68 years]). Patients were divided into two groups, with veins 1 mm or less in diameter (group 1, n = 50) or veins 3 mm or less in diameter (group 2, n = 51). Group 1 was treated with Sotradecol (STD) 0.25%, and group 2 with STD 0.50%. In each patient, an area of varicosities was selected and divided into halves. One half was randomized to microthrombectomy and the other half served as control. Microthrombectomy was performed 1 to 3 weeks after treatment in the randomized half. Standard photographs were obtained before and 16 weeks after treatment, and were evaluated by three independent reviewers who were blinded to treatment assignments. Each reviewer received an identical set of pretreatment and posttreatment 10 x 15-cm color photographs of the study area, and completed a scoring sheet. Average of the scores was used to evaluate primary (pigmentation) and secondary (overall clinical improvement) end points. The paired t test and chi-square test were used for statistical analysis. RESULTS In group 1, microthrombectomized areas had statistically significant less pigmentation (P =.0047) and better overall clinical improvement scores (P =.0002) compared with the control side. In group 2 there was no significant difference between the two areas, but patients reported significant relief of pain and inflammation associated with postsclerotherapy thrombophlebitis. CONCLUSION In veins 1 mm or smaller, microthrombectomy reduced pigmentation and improved overall clinical results. In veins 3 mm or smaller, statistical significance was not achieved, but thrombectomy resulted in faster resolution of the postsclerotherapy pain and inflammation. On the basis of these results, microthrombectomy after sclerotherapy is recommended.

Traumatic brain injury and severe uncontrolled haemorrhage with short delay pre-hospital resuscitation in a swine model

INTRODUCTION Unavailability of blood (and oxygen delivery) for pre-hospital resuscitation in haemorrhagic shock patients are major problems, supporting the importance for novel resuscitation strategies. In a combined polytrauma model of uncontrolled haemorrhage and traumatic brain injury (TBI) in swine, we investigated if pre-hospital administration of the haemoglobin based oxygen carrier HBOC-201 will improve tissue oxygenation and physiologic parameters compared to Lactated Ringers (LR) solution. MATERIALS AND METHODS Anaesthetised Yorkshire swine underwent fluid-percussion TBI and Grade III liver laceration. During a 30-min pre-hospital phase, the animals were resuscitated with a single infusion of HBOC-201, LR solution, or nothing (NON). Upon hospital arrival, the animals were given blood or normal saline as needed. Surviving animals were euthanised 6h post-injury. Cerebral blood flow was measured by microsphere injection, and pathology was assessed by gross observation and immunohistochemical analysis. RESULTS Mean TBI force (2.4±0.1atm) (means±standard error of the mean) and blood loss (22.5±1.7mL/kg) were similar between groups. Survival at the 6h endpoint was similar in all groups (∼50%). Cerebral perfusion pressure (CPP) and brain tissue oxygen tension were significantly greater in HBOC-201 as compared with LR animals (p<0.005). Mean arterial pressure (MAP) and mean pulmonary artery pressure (MPAP) were not significantly different amongst groups. Blood transfusion requirements were delayed in HBOC-201 animals. Animals treated with HBOC-201 or LR showed no immunohistopathological differences in glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP-2). Severity of subarachnoid and intraparenchymal haemorrhages were similar for HBOC and LR groups. CONCLUSION In this polytrauma swine model of uncontrolled haemorrhage and TBI with a 30-min delay to hospital arrival, pre-hospital resuscitation with one bolus of HBOC-201 indicated short term benefits in systemic and cerebrovascular physiological parameters. True clinical benefits of this strategy need to be confirmed on TBI and haemorrhagic shock patients.

Congenital vascular malformations: When and how to treat them

Congenital vascular malformations may involve arterial, venous, and lymphatic structures, can present in a variety of forms, and present many diagnostic and therapeutic challenges. Two-thirds of all congenital vascular malformations are predominantly venous, and their management will be emphasized in this article, because of the focus of this issue. The majority of the venous malformations are asymptomatic and should be treated conservatively. However, the clinical presentation of venous malformations associated with lymphatic anomalies is variable, and management may be more challenging. The diagnosis and management of arteriovenous malformations is straightforward. Selective catheter-directed embolization of the feeding arteries, occasionally followed by tumor excision, is the treatment of choice. Hemangiomas often will grow rapidly and then begin to regress. When they produce troublesome symptoms and are well localized, they should be excised. Deeply seated or diffuse malformations require a complete diagnostic evaluation to select the most appropriate time and type of intervention. Both our own experience and that of others can provided some basis for therapeutic recommendations in treating the different vascular malformations.

Sodium nitroprusside ameliorates systemic but not pulmonary HBOC-201-induced vasoconstriction: an exploratory study in a swine controlled haemorrhage model.

BACKGROUND Vasoconstriction is a side effect that may prevent the use of haemoglobin based oxygen carrier (HBOC) as blood substitute. Therefore, we tested the hypothesis that the NO donor, sodium nitroprusside (SNP), would mitigate systemic and pulmonary hypertension associated with HBOC-201 in a simple controlled haemorrhage swine model. METHODS After 55% estimated blood volume withdrawal through a venous catheter, invasively anesthetized and instrumented animals were resuscitated with three 10 ml/kg infusions of either HBOC-201 or Hextend (HEX) with or without 0.8 μg/kg/min SNP (infused concomitantly via different lines). Haemodynamics, direct and indirect measures of tissue oxygenation, and coagulation were measured for 2h. RESULTS Haemorrhage caused a state of shock manifested by hypotension and base deficit. HBOC-201 resuscitation resulted in higher systemic (p<0.0001) and pulmonary (p<0.002) blood pressure than with HEX. Elevation of systemic (p<0.0001) but not pulmonary (p>0.05) arterial pressure was attenuated by co-infusion of SNP, without significant group differences in haemodynamics, tissue oxygenation, platelet function, coagulation, methaemoglobin, or survival (p>0.05). CONCLUSION In swine with haemorrhagic shock, co-administration of the NO donor, SNP, effectively and safely reduces HBOC-201-related systemic but not pulmonary vasoactivity. Interestingly, co-administration of the vasodilator SNP with HEX had no deleterious effects in comparison with HEX alone.

Dose Response of Sodium Nitrite on Vasoactivity Associated with HBOC-201 in a Swine Model of Controlled Hemorrhage

Abstract Sodium nitrite (NaNO2) was evaluated in a 55% EBV hemorrhage swine model to mitigate the increased blood pressure due to HBOC-201. Animals were resuscitated by three 10ml/kg infusions of either HBOC-201 or Hextend with and without NaNO2. All vital signs, coagulation and blood chemistry were measured for 2hr. HBOC-201-vasoconstriction was attenuated only after the first 10.8μmol/kg NaNO2 infusion. Complete abolition was obtained with the highest 3 NaNO2 dose, but side effects were observed. There was no reduction in platelet function due to NaNO2. NaNO2 ability to reduce HBOC-201 vasoactivity was transient and 10.8μmol/kg NaNO2 seems an acceptable dose for further investigation.

Hematologic effects of recombinant factor Viia combined with hemoglobin-based oxygen carrier-201 for prehospital resuscitation of swine with severe uncontrolled hemorrhage due to liver injury

The combination of traumatic injury, hemorrhage, and fluid resuscitation results in consumption and dilution of coagulation factors, adversely impacting hematology outcome in trauma patients. The hemostatic effects of escalating doses of recombinant factor VIIa added to hemoglobin-based oxygen carrier-201 were assessed as prehospital fluid resuscitation in swine with severe uncontrolled hemorrhage. Swine underwent liver injury causing severe uncontrolled hemorrhage and shock. During a 4-h prehospital phase, either hypotensive or tachycardic, or both, animals were resuscitated with hemoglobin-based oxygen carrier-201 without (0×) or with escalating doses of recombinant factor VIIa [90 μg/kg (1×), 180 μg/kg (2×), or 360 μg/kg (4×)]. The animals received one initial full dose of 10 ml/kg at 15 min and up to four doses of 5 ml/kg thereafter. From 4 to 72 h (hospital phase), animals received either transfusions or isotonic saline or both as needed. Hematology profile (complete blood count), thromboelastography, in-vitro bleeding (platelet function analyzer), and coagulation (prothrombin time) were measured and the results were compared using mixed statistical models. In all groups, dilutional coagulopathy was evidenced by reduced hematocrit, platelets, and thromboelastography-maximum amplitude, and increased platelet function analyzer closure time and thromboelastography-reaction time. During the prehospital phase, hemoglobin-based oxygen carrier-201 restored hemoglobin in all groups. Recombinant factor VIIa decreased prothrombin time in recombinant factor VIIa groups compared with the hemoglobin-based oxygen carrier-201 group (P < 0.01). Unexpectedly, increasing recombinant factor VIIa dosage tended to increase fluid requirement (P > 0.05). Compared with hemoglobin-based oxygen carrier, 1× recombinant factor VIIa tended to decrease blood loss, lactate and thromboelastography-reaction time at 24 h but the 4× group increased these parameters. Platelets and thromboelastography-maximum amplitude decreased (P < 0.01) with the 4× group. In swine with severe uncontrolled hemorrhage, prehospital resuscitation with escalating doses of recombinant factor VIIa in combination with hemoglobin-based oxygen carrier-201 did not change survival or hemostasis. However, there were trends toward possible benefits of low recombinant factor VIIa doses, whereas high recombinant factor VIIa doses adversely affected hemostasis.

Perfluorocarbon NVX-108 increased cerebral oxygen tension after traumatic brain injury in rats.

BACKGROUND Hypoxia is a critical secondary injury mechanism in traumatic brain injury (TBI), and early intervention to alleviate post-TBI hypoxia may be beneficial. NVX-108, a dodecafluoropentane perfluorocarbon, was screened for its ability to increase brain tissue oxygen tension (PbtO2) when administered soon after TBI. METHODS Ketamine-acepromazine anesthetized rats ventilated with 40% oxygen underwent moderate controlled cortical impact (CCI)-TBI at time 0 (T0). Rats received either no treatment (NON, n=8) or 0.5 ml/kg intravenous (IV) NVX-108 (NVX, n=9) at T15 (15 min after TBI) and T75. RESULTS Baseline cortical PbtO2 was 28±3 mm Hg and CCI-TBI resulted in a 46±6% reduction in PbtO2 at T15 (P<0.001). Significant differences in time-group interactions (P=0.013) were found when comparing either absolute or percentage change of PbtO2 to post-injury (mixed-model ANOVA) suggesting that administration of NVX-108 increased PbtO2 above injury levels while it remained depressed in the NON group. Specifically in the NVX group, PbtO2 increased to a peak 143% of T15 (P=0.02) 60 min after completion of NVX-108 injection (T135). Systemic blood pressure was not different between the groups. CONCLUSION NVX-108 caused an increase in PbtO2 following CCI-TBI in rats and should be evaluated further as a possible immediate treatment for TBI.

Effects of N-Acetyl-L-Cysteine and Hyaluronic Acid on HBOC-201- Induced Systemic and Cerebral Vasoconstriction in the Rat

Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.

Brain hypoxia is exacerbated in hypobaria during aeromedical evacuation in swine with traumatic brain injury.

BACKGROUND There is inadequate information on the physiologic effects of aeromedical evacuation on wounded war fighters with traumatic brain injury (TBI). At altitudes of 8,000 ft, the inspired oxygen is lower than standard sea level values. In troops experiencing TBI, this reduced oxygen may worsen or cause secondary brain injury. We tested the hypothesis that the effects of prolonged aeromedical evacuation on critical neurophysiologic parameters (i.e., brain oxygenation [PbtO2]) of swine with a fluid percussion injury/TBI would be detrimental compared with ground (normobaric) transport. METHODS Yorkshire swine underwent fluid percussion injury/TBI with pretransport stabilization before being randomized to a 4-hour aeromedical transport at simulated flight altitude of 8,000 ft (HYPO, n = 8) or normobaric ground transport (NORMO, n = 8). Physiologic measurements (i.e., PbtO2, cerebral perfusion pressure, intracranial pressure, regional cerebral blood flow, mean arterial blood pressure, and oxygen transport variables) were analyzed. RESULTS Survival was equivalent between groups. Measurements were similar in both groups at all phases up to and including onset of flight. During the flight, PbtO2, cerebral perfusion pressure, and mean arterial blood pressure were significantly lower in the HYPO than in the NORMO group. At the end of flight, regional cerebral blood flow was lower in the HYPO than in the NORMO group. Other parameters such as intracranial pressure, cardiac output, and mean pulmonary artery pressure were not significantly different between the two groups. CONCLUSION A 4-hour aeromedical evacuation at a simulated flight altitude of 8,000 ft caused a notable reduction in neurophysiologic parameters compared with normobaric conditions in this TBI swine model. Results suggest that hypobaric conditions exacerbate cerebral hypoxia and may worsen TBI in casualties already in critical condition.

Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats.

The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction. The aim of this study was to assess vasoactive effects of OxyVita C on systemic blood pressures and cerebral pial arteriole diameters. Anesthetized healthy rats received four intravenous (IV) infusions of an increasing dose of OxyVita C (2, 25, 50, 100 mg/kg) and hemodynamic parameters and pial arteriolar diameters were measured pre- and post-infusion. Normal saline was used as a volume-matched control. Systemic blood pressures increased (P ≤ 0.05) with increasing doses of OxyVita C, but not with saline. There was no vasoconstriction in small (<50 µm) and medium-sized (50–100 µm) pial arterioles in the OxyVita C group. In contrast, small and medium-sized pial arterioles vasoconstricted in the control group. Compared to saline, OxyVita C showed no cerebral vasoconstriction after any of the four doses evaluated in this rat model despite increases in blood pressure.