Activation of the stress protein response prevents the development of pulmonary edema by inhibiting VEGF cell signaling

2006 Jun 22 - Research Abstract

Activation of the stress protein response prevents the development of pulmonary edema by inhibiting VEGF cell signaling in a model of lung ischemia-reperfusion injury in rats.

Godzich M, Hodnett M, Frank JA, Su G, Pespeni M, Angel A, Howard MB, Matthay MA, Pittet JF.

*Laboratory of Surgical Research, Departments of Anesthesia, Surgery, andMedicine and Cardiovascular Research Institute, University of California, San Francisco, California, USA.

Lung endothelial damage is a characteristic morphological feature of ischemia-reperfusion (I/R) injury, although the molecular steps involved in the loss of endothelial integrity are still poorly understood. We tested the hypothesis that the activation of vascular endothelial growth factor (VEGF) cell signaling would be responsible for the increase in lung vascular permeability seen early after the onset of I/R in rats.

Furthermore, we hypothesized that the I/R-induced pulmonary edema would be significantly attenuated in rats by the activation of the stress protein response. Pretreatment with Ad Flk-1, an adenovirus encoding for the soluble VEGF receptor type II, prevented I/R-mediated increase in lung vascular permeability in rats.

Furthermore, the I/R-induced lung injury was significantly decreased by prior activation of the stress protein response with geldanamycin or pyrrolidine dithiocarbamate. In vitro studies demonstrated that VEGF caused an increase in protein permeability across primary cultures of bovine macro- and microvascular lung endothelial cell monolayers that were associated with a phosphorylation of VE- and E-cadherin and the formation of actin stress fibers.

Activation of the stress protein response prevented the VEGF-mediated changes in protein permeability across these cell monolayers and reduced the phosphorylation of VE-and E-cadherins, as well as the formation of actin stress fibers in these cells. .--Godzich, M., Hodnett, M., Frank, J. A., Su, G., Pespeni, M., Angel, A., Howard, M. B., Matthay, M. A., Pitte, J. F.

Activation of the stress protein response prevents the development of pulmonary edema by inhibiting VEGF cell signaling in a model of lung ischemia-reperfusion injury in rats.

PMID: 16793871 [PubMed - as supplied by publisher]

Severe Gestational Edema

Severe Gestational Edema

Dianne Reynolds, CNM, MSN
J Midwifery Womens Health 48(2):146-148, 2003. © 2003 Elsevier Science, Inc.
Posted 05/14/2003

Abstract

Lower extremity edema is an almost universal finding in late pregnancy, occurring secondary to increased venous pressure in the legs, obstruction of lymphatic flow, and reduced plasma colloid osmotic pressure.[1] Varney describes gestational edema as the development of an excessive accumulation of fluid in the tissues without coexisting hypertension or proteinuria.[2] Midwives are familiar with this common condition in an otherwise uncomplicated pregnancy and are comfortable reassuring clients that lower extremity edema is non-pathologic. The patient with severe lower extremity edema, however, presents the provider with a clinical challenge. Is the presenting symptom a sign of an underlying disease process, or simply a normal physiologic process with extreme manifestation/expression? Lower extremity edema that rises to include the labia presents an intrapartum challenge of managing tissue integrity during the birth. A case of severe gestational edema is reported. Discussion explores broader considerations in differential diagnosis and management.

Case Presentation

A 34-year-old Peruvian G2P1001 presented for care at 12 weeks. Family, medical, surgical, and gynecologic histories were unremarkable. She stood approximately 4'10" tall and had an intake weight of 115 lb. Obstetric history included a previous spontaneous vaginal delivery of a 3000-g daughter 9 years ago at home in Peru without problems. She has been living in the United States for several years with her (Peruvian) husband, mother-in-law, and 9-year-old daughter. She is a full-time mother and homemaker.

Her prenatal labs were normal. Hemoglobin (Hgb) was 12 g/dL in the first trimester, and 11.2 g/dL at 29 weeks. The 1-hour glucose challenge was 109. Her prenatal course was uneventful until 29 weeks when she was noted to have pedal edema, but no proteinuria.

Blood pressure was 102/62. Subsequent weekly visits continued to note pedal edema, with negative urine protein and normal blood pressures. Weight gain was 1 lb per week from 17 to 29 weeks.

At the 35-week visit, pedal edema was more remarkable with +2 pitting and a 4-lb weight gain in 2 weeks. Her blood pressure was100/68 with negative urine protein. She was advised to elevate her legs for 20 minutes every 2 hours, reduce sodium, and increase water intake. At the 37-week visit, her weight gain showed 6 lb in 2 weeks, now with +3 pitting "lower leg" and pedal edema, blood pressure of 118/72, and negative urine protein. Again she was advised to elevate her legs and decrease sodium intake (specific counseling guidelines were not specified).

This woman was admitted to the labor floor at 40 weeks' gestation with a history of spontaneous rupture of clear fluid 5 hours prior to arrival and uterine contractions every 10 minutes. Her admission physical was unremarkable: heart auscultation of regular rate and rhythm, without murmur; lungs were clear bilaterally without rales, rhonchi, or wheezes, and breathing was unlabored. Her cervix was 4 cm dilated, 100% effaced with the vertex at 0 station. The estimated fetal weight was 3200 g. Most notable was the +3 pitting lower extremity and labial edema, which she reported had worsened over the past 2 weeks. The skin was taut and shiny, she had difficulty walking, and vaginal examinations were challenging and painful.

Admission blood pressure was 119/76, and there was no proteinuria. She denied headache, visual changes, or right upper quadrant abdominal pain (symptoms of preeclampsia). Laboratory results were obtained and were within normal limits (blood urea nitrogen [BUN] 6, creatinine 0.6, uric acid 3.6, serum glutamic-oxaloacetic transaminase [SGOT] 20, white blood cell [WBC] 8, Hgb10.6, and platelets 174).

The first stage of labor progressed slowly for a secundigravida, dilating at a rate of less than 1 cm per hour after an epidural was placed at 4-cm dilation, followed by Pitocin augmentation. The second stage of labor included 1 hour of passive descent, followed by 2 hours of active pushing. The challenge of delivering through such an edematous, taut vulva was apparent. Counter pressure and support using cool water compresses were applied in an attempt to minimize the possibility of extensive trauma to the edematous vulva from the emerging head. She delivered a healthy 3980-g daughter over an irregular 2nd degree left vaginal-perineal laceration, which was repaired by using 3-0 Vicryl with excellent results.

She was discharged on the second postpartum day. At discharge, the perineal repair was intact and her labial edema had resolved from severe to slight. There was no evidence of infection or hematoma. The examination results of her extremities were not documented.

Five days postpartum, the woman returned to the hospital triage facility, reporting continued lower leg swelling. The examination revealed bilateral, +3 pitting edema from her feet to the inferior aspects of her knees. Both legs were symmetrically tense and erythematous. Homan's sign was negative and there was no focal tenderness. Blood pressure, pulse, and temperature were within normal limits. Basic examination of the heart, lungs, and abdomen were normal.

In the review of differential diagnosis, it was concluded that cellulitis and deep vein thrombosis (DVT) were considered highly unlikely, because neither process would be so bilaterally symmetrical. The plan was for conservative management, and she was advised to follow up in 1 week. The client did not keep her follow-up appointment nor her 6-week postpartum appointment.

Discussion

Edema, the perceptible expansion of the interstitial fluid volume, results from alterations in the basic physiologic mechanisms governing fluid balance.[3] The hydrostatic pressure within the vascular system and the colloid oncotic pressure in the interstitial fluid promote movement of fluid from the vascular to the extravascular space. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillary and by way of the lymphatic system.[4] Intravascular oncotic pressure (facilitated by plasma proteins) also assists in the movement of fluid back into the vessels.[5]

Gestational edema occurs in late pregnancy secondary to increased venous congestion in the legs caused by pressure exerted mechanically by the uterus onto the inferior vena cava and iliac veins.[6] Reduced plasma colloid oncotic pressure and obstruction of lymphatic flow impair reabsorption of fluid into the intravascular compartment.

Although severe edema in pregnancy is uncommon, review of the literature reveals its complex nature. The differential diagnoses include diseases and disorders that are either caused by pregnancy or aggravated by it.

Systemic diseases such as malnutrition, renal or hepatic disease, preeclampsia, diabetes, or congestive heart failure should be considered.[7] Labial edema can result from local trauma, infection (genital herpes or other sexually transmitted infections, candidiasis), inflammation, or allergic reaction. Because there are documented cases of maternal death associated with vulvar edema, pregnant and postpartum women with this condition merit special attention.[8, 9]

When the essentially healthy pregnant woman presents with severe lower extremity and/or labial edema, the etiology should be explored by thorough history and physical examination (H&P). Laboratory and other diagnostic tests should focus on the most likely causes suspected from the findings noted in the H&P.
Initial physical assessment should evaluate the extent of the edema. The circumference of the legs should be measured from a defined, predetermined reference point to compare symmetry and course of progression or resolution.[5]

"Pitting" is the term used to describe the indentation caused when pressure is applied to the skin, forcing fluids into the underlying tissue. It occurs when there is an increased amount of low protein fluid in the interstitial space and is associated with disorders caused by high capillary filtration (DVT, chronic venous insufficiency, or venous obstruction) or hypoalbuminemia. Pitting is a subjective assessment using the grading scale of 1+ for mild and up to 4+ for deep pitting. Given the subjective nature of this assessment, continuity of provider is ideal when making successive assessments.[5]

Nutritional assessment should include investigation of daily caloric intake, adequacy of all food groups, and most specifically, protein intake. Optimal calorie and protein recommendations should be calculated for each individual, giving specific instructions regarding nutritional needs as determined by ideal weight and activity level. Nutritional counseling is most effective when the woman's established dietary patterns and culturally determined preferences are considered (in this case Peruvian). Weight gain should be monitored. A total serum albumin level, which is normally between 3.5 and 5.0 g/dL, may reveal deficiencies in protein intake.

Edema secondary to renal disease can be recognized by appropriate renal function tests (BUN, creatinine, uric acid), and evaluation of protein loss by urinalysis. Likewise, liver function can be assessed by checking liver function tests. The abdominal examination should include liver margin edge location and any tenderness to palpation.

The client should also be assessed for signs and symptoms of preeclampsia: headache, abdominal pain, or visual changes. Monitor blood pressure and renal and liver function. Routine diabetic screening will assess disorders of carbohydrate metabolism. When diabetes in pregnancy is associated with severe edema, this should prompt investigation of associated sequelae, such as microvascular damage in the liver or kidneys.

In pregnancy, adequate tissue perfusion requires an increase in cardiac output. Although this increased cardiac output can be sustained by a normally functioning heart, a woman with underlying heart disease may manifest symptoms of compromise. Clinical manifestations of heart failure include dyspnea, orthopnea, fatigue, and weakness. Physical findings include discomfort when lying flat, decreased pulse pressure, elevated diastolic blood pressure. Pulmonary rales signify pulmonary edema. Performance of an echocardiogram may be indicated if cardiac compromise is suspected.[4]

Deep venous thrombophlebitis is a serious disorder that occurs in 1 in 2000 pregnancies. Although most venous thrombi are asymptomatic, one third of patients present with the classic symptoms of pain, edema, and a positive Homan's sign.[3, 10] Edema in this case is usually asymmetric. Ultrasound is the most accurate noninvasive study for the diagnosis of lower extremity deep vein thrombosis.[11]

Labial edema can result from trauma, infection, inflammation, or allergic reaction. These possible etiologies should be explored thoroughly by history and physical examination. Pelvic examination should note degree of vulvar edema, tissue integrity, color, and discharge. Labial edema is commonly reported in association with conditions such as preeclampsia and prolonged second stage. This condition has also been reported in association with use of intravenous tocolytics (magnesium sulfate, nifedipine, terbutaline).[12, 13] The vulva is the most dependent area of the body in women undergoing bed rest, rendering it susceptible to the pressure-volume dynamic of pregnancy that can lead to a large accumulation of fluid in the vulvar or labial tissue.

There have been five documented cases of maternal death associated with severe postpartum vulvar edema. Although the causes of these deaths are unclear, it is speculated that they were either endotoxic or immunologic in nature. All cases were associated with marked leukocytosis.[8]

When a thorough investigation determines the diagnosis of gestational edema, immersion therapy in shoulder deep water may be helpful. Katz et al.[14] have suggested that this treatment hydrostatically forces extravascular fluid into the blood vessels, producing an intravascular infusion that starts soon after immersion has begun. There are many unexplored issues regarding immersion therapy during pregnancy, including optimal frequency, water depth and temperature, and duration of effect.

Conclusion

In the case presented, the patient had progressively worsening lower extremity edema starting at 29 weeks' gestation which became severe, with involvement of her labia majora by term. Her history, physical, and laboratory tests did not lead to suspicion of more serious pathophysiology. This woman is of small stature, growing a baby considerably larger than her first, which resulted in extreme venous congestion and a protracted labor.

Severe lower extremity edema should prompt the clinician to consider the potential pathophysiology of this condition. If the data collected through history, physical, and laboratory analysis excludes the more serious diagnoses, then idiopathic gestational edema is the likely etiology. Midwifery recommendations for management throughout the childbearing and recovery period warrant further study.

References

Gabbe SG, Niebyl JR and Simpson JL, eds. Obstetrics: normal and problem pregnancies, 3rd ed. New York (NY): Churchill Livingstone, 1996.

Varney H, ed. Varney's midwifery, Jones and Bartlett Publishers, Sudbury (MA) 1997.
Powell AA, Armstrong MA. Peripheral edema. Am Fam Physician, 1997, 55;1721-1726.

Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL et al., eds. Harrison's principles of internal medicine, 14th ed., vol. 1. New York (NY): McGraw-Hill Health Professions Division, 1998.

Yale SH, Mazza JJ. Approach to diagnosing lower extremity edema. Compr Ther, 2001, 27;242-252.

Bracero LA, Didomenico A. Massive vulvar edema complicating preeclampsia: a management dilemma. J Perinatol, 1991, 11;122-125.

Jakobi P, Friedman M, Goldstein I, Zaidise I, Itskovitz-Eldor J. Massive vulvar edema in pregnancy: a case report. J Reprod Med, 1995, 40;479-481.

Finkler NJ, Safon LE, Ryan KJ. Bilateral postpartum vulvar edema associated with maternal death. Am J Obstet Gynecol, 1997, 156;1188-1189.

Trice L, Bennert H, Stubblefield PG. Massive vulvar edema complicating tocolysis in a patient with twins: a case report. J Reprod Med, 1996, 41;121-124.

Spritzer CE, Evans AC, Kay HH. Magnetic resonance imaging of deep venous thrombosis in pregnant women with lower extremity edema. Obstet Gynecol, 1995, 85;603-607.

Rosen CL, Tracy JA. The diagnosis and lower extremity deep venous throbosis. Emerg Med Clin North Am 2001;19.

Awwad JT, Khalil AM, Aswad NK, Suidan FJ, Karam KS. Labial edema in pregnancy: a case report. J Reprod Med, 1994, 39;921-922.

Brittain C, Carlson JW, Gehlbach DL, Robertson AW. A case report of massive vulvar edema during tocolysis of preterm labor. Am J Obstet Gynecol, 1991, 165;420-422.

Katz VL, Ryder RM, Cafalo RC, Carmichael SC, Goolsby R. A comparison of bedrest and immersion for treating the edema of pregnancy. Obstet Gynecol, 1990, 75;147.

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NEW LYMPHEDEMA PEOPLE FORUMS

Remember, this was the week with the date 06/06/06??
With only an hours notice GoDaddy, our fee-paid host of Lymphedema
People abruptly decided our forums were gobbling up too much space,
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As a result, we had to put in completely new ones.

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THE NEW FORUMS ARE UP AND RUNNING!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Our new forums represent a significant upgrade with many new
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If you were a member of our old forums, we would love to have you
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Please go ahead and reregister. We were hoping to automatically
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I will be working feverishly this weekend to see that all the
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Bone Marrow Edema in Osteoporotic Vertebral Compression Fractures

Bone Marrow Edema in Osteoporotic Vertebral Compression Fractures after Percutaneous Vertebroplasty and Relation with Clinical Outcome

M.H.J. Voormolena, W.J. van Rooija, Y. van der Graafc, P.N.M. Lohlea, L.E.H. Lampmanna, J.R. Juttmannb and M. Sluzewskia

a Department of Radiology, St. Elisabeth Ziekenhuis, Tilburg, the Netherlandsb Department of Internal Medicine, St. Elisabeth Ziekenhuis, Tilburg, the Netherlandsc Department of Clinical Epidemiology, Julius Centre for Health Sciences and Primary Care, Utrecht, the Netherlands

Address correspondence to Maurits Voormolen, MD, Department of Radiology, St Elisabeth Ziekenhuis, PO Box 90151, 5000 LC Tilburg, the Netherlands

BACKGROUND AND PURPOSE:

Little is known about the evolution of bone marrow edema (BME) in osteoporotic vertebral compression fractures (VCF) after percutaneous vertebroplasty (PV) or about its relation with relief of pain. In this study, we prospectively assessed changes in BME with MR imaging at 3, 6, and 12 months after PV and related changes in BME with pain evolution and analgesic use over time.

METHODS:

BME percentage was assessed in 64 patients after PV of 89 VCF with serial MR imaging follow-up at 3, 6, and 12 months. Pain was assessed before PV and at every follow-up interval by visual analog scale for pain and type of analgesic used. Relation between changes in BME and pain evolution was assessed in a subgroup of 31 patients with a single treated VCF and neither new VCF at follow-up nor pain at another untreated level.

RESULTS:

BME gradually decreased over time. At 1 year after PV, 29% of treated VCF still demonstrated BME. Once BME disappeared, it did not return. Pain relief was most striking the first 3 months after PV and remained constant thereafter. There was no relation between relief of pain and extent, presence, or absence of BME after PV.

CONCLUSION:

A gradual decrease of BME in osteoporotic VCF treated with PV is apparent during 12 months of MR imaging follow-up. Decrease of BME is unrelated to relief of pain.

American Journal of Neuroradiology