Biomarker analysis in polycythemia vera under interferon-alpha treatment: clonality, EEC, PRV-1, and JAK2 V617F.

Three consecutive polycythemia vera (PV) patients were analyzed before and during pegylated-interferon (rIFNalpha) treatment for the following markers: (1) granulocyte and CD34(+) cell clonality, (2) Jak2V617F expression, (3) PRV-1 mRNA overexpression, and (4) Epo-independent colony (EEC) growth. Before rIFNalpha therapy, all patients displayed clonal hematopoiesis, 100% Jak2V617F expression as well as PRV-1 overexpression, and EEC growth. After rIFNalpha treatment, all three patients demonstrated polyclonal hematopoiesis. Nonetheless, Jak2V617F expression, PRV-1 overexpression, and EEC-growth remained detectable, albeit at lower levels. We conclude that reemergence of polyclonal hematopoiesis after rIFNalpha treatment may be achieved in a substantial proportion of patients. However, this does not constitute elimination of the PV clone. These data demonstrate the usefulness of novel markers in monitoring minimal residual disease and caution against discontinuation of rIFNalpha treatment after hematologic remission. Long-term follow-up of large patient cohorts is required to determine whether rIFNalpha treatment can cause complete molecular remissions in PV.

STAT3 is constitutively active in some patients with Polycythemia rubra vera.

OBJECTIVE: Polycythemia vera is a clonal stem cell disorder characterized by hyperproliferation of the erythroid, myeloid, and megakaryocytic lineages. While it has been shown that progenitor cells of P. vera patients are hypersensitive to several growth factors including erythropoietin, insulin-like growth factor-1, thrombopoietin, interleukin-3, and granulocyte/monocyte colony-stimulating factor, the molecular pathogenesis of this disease remains unknown. Growth factor hypersensitivity could be mediated by changes in signal transduction pathways. We therefore investigated a common downstream effector of cytokines, the signal transducers and activators of transcription (STATs). A constitutive activation of STAT factors could explain the increased proliferation of P. vera cells even in the absence of growth factor stimulation. METHODS: Peripheral granulocytes from patients with P. vera and from healthy volunteers were assayed for STAT1, 3, and 5 DNA binding by electrophoretic mobility shift assay. RESULTS: Four of 14 P. vera patients analyzed showed constitutive STAT3 DNA binding in unstimulated peripheral granulocytes, while none of the 17 healthy volunteers tested did. None of the subjects showed constitutive STAT1 or STAT5 activity. Western blotting demonstrated that, in the three patients, STAT3 is constitutively phosphorylated on Tyr 705, whereas it is unphosphorylated in the other patients and in controls. Interestingly, constitutive STAT3 activity did not correlate with the duration of disease or the treatment regimen. It was observed in a recently diagnosed patient and in two patients treated only with phlebotomy. CONCLUSION: Our data suggest that constitutive phosphorylation and activation of STAT3 is not a secondary event induced by mutagenizing agents or by prolonged hyperproliferation of hematopoietic cells, but rather represents a primary molecular aberration. Constitutively active STAT3 may contribute to the growth factor hypersensitivity of P. vera cells.

Mortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure.

OBJECTIVE: To investigate the relationship between the period of mechanical ventilation before extracorporeal life support and survival in patients with respiratory failure. DESIGN: Retrospective review. SETTING: Surgical intensive care unit at a university medical center. PATIENTS: Thirty-six consecutive adult patients with severe respiratory failure managed with extracorporeal life support. INTERVENTIONS: Extracorporeal life support was utilized in 36 acute respiratory failure adult patients with a variety of diagnoses and an estimated mortality rate of > 90%. Management protocols were followed before and during extracorporeal life support. The 36 patients were physiologically similar before extracorporeal life support was initiated: shunt of 48 +/- 17%; F10(2) of 1.0 +/- 0.1; peak inspiratory pressure of 56 +/- 16 cm H2O; positive end-expiratory pressure of 14 +/- 6 cm H2O; and respiratory rate of 23 +/- 10 breaths/ min. Ventilation was utilized for 1 to 17 days before extracorporeal life support. Typical lung rest settings during extracorporeal life support were F10(2) of 0.40, peak inspiratory pressure of 30 cm H2O, positive end-expiratory pressure of 10 cm H2O, and respiratory rate of 6 breaths/min. Death was almost always secondary to end-stage pulmonary failure. MEASUREMENTS AND MAIN RESULTS: Survival (hospital discharge) in these 36 patients was inversely associated with the number of days of preextracorporeal life support ventilation, with a 50% mortality rate predicted by logistic regression after 5 days of mechanical ventilation. The overall survival rate was 18 (50.0%) of 36 patients. CONCLUSIONS: In severe acute respiratory failure treated with lung rest and extracorporeal life support, a predicted 50% mortality rate was associated with 5 days of preextracorporeal life support mechanical ventilation.

Outcome of reoperative valve surgery via right thoracotomy.

BACKGROUND: The rate of patients being referred for mitral or tricuspid valve surgery after previous cardiac surgery is expected to increase. Reoperative median sternotomy has known risks, including injury to or embolism from prior grafts, sternal dehiscence, phrenic nerve injury, excessive hemorrhage, and inadvertent cardiac injury leading to morbidity and mortality. METHODS AND RESULTS: To avoid these problems, the right thoracotomy approach for reoperative mitral or tricuspid valve surgery was used in 62 patients from January 1990 to September 1995. Average patient age was 66 +/- 12 years. Previous operations included: coronary artery bypass graft, 31; mitral valve surgery, 26 (repair, 12, replacement, 14); and aortic valve surgery, 10. Patients were cannulated via the ascending aorta or common femoral artery with bicaval venous drainage. Systemic cooling and fibrillatory arrest were used. Operations performed included mitral valve repair in 27 patients; mitral valve replacement in 18; prosthetic mitral valve replacement in 14; repair of prosthetic mitral valve leak in 2; and tricuspid valve repair in 5. There was 1 intraoperative death and 4 other hospital deaths; 30-day hospital mortality was 6.4%. Complications were uncommon; only 1 patient required reexploration for bleeding. There have been 4 late deaths, and at a mean follow-up of 27 months (range, 1 to 69 months), survivors are in New York Heart Association class I or II. CONCLUSIONS: Right thoracotomy is a safe, feasible alternative to median sternotomy for selected reoperative mitral valve patients and should be considered whenever repeat sternotomy could prove hazardous.

Extracorporeal life support for respiratory failure after multiple trauma.

Respiratory failure may complicate multiple trauma and can add significant morbidity, mortality, and cost to the care of such patients. We used extracorporeal life support (ECLS) to treat 24 patients with multiple trauma who, after their injury, developed respiratory failure refractory to conventional ventilatory management. Injuries in these patients were the result of motor vehicle crashes (16 patients), pedestrian versus car collisions (3 patients), gunshots (2 patients), stabs (1 patient), and a recreational vehicle crash (1 patient). Patients were placed on venovenous or venoarterial ECLS, using continuous systemic anticoagulation with heparin, and percutaneous cannulation where possible. Average time on ECLS was 287 +/- 43 hours (12 +/- 1.8 days). The major complication was bleeding, which occurred in 75% of patients. Fifteen patients survived to be discharged from the hospital (63% survival). Early intervention (mechanical ventilation < or = 5 days prior to ECLS) was associated with good outcome. Despite risks of anticoagulation in patients with multiple injuries, ECLS can be life-saving in cases of respiratory failure refractory to conventional mechanical ventilation.

Effect of extracorporeal life support on survival when applied to all patients with congenital diaphragmatic hernia.

Extracorporeal life support (ECLS) has been used for neonates with congenital diaphragmatic hernia (CDH) and respiratory failure at the authors' hospital since June 1981. In 1988, criteria for inclusion in ECLS were broadened to include "nonhoneymoon" infants (honeymoon: best postductal PaO2 of > 50 mm Hg). To evaluate the impact of this approach on the treatment of CDH, the authors reviewed the records of all newborns managed at their institution, since the availability of ECLS in 1981, who were symptomatic with CDH in the first 24 hours of life (n = 111). The patients were divided chronologically into two groups: 1981 to 1987 (early ECLS, n = 36) and 1988 to 1993 (expanded ECLS, n = 75). The data demonstrate that the number of CDH patients managed at our institution each year has increased (1981 to 1987 = 6, 1988 to 1993 = 14) as has the severity of associated respiratory insufficiency (% of patients with best PaO2 of < or = 50 mm Hg: 1981 to 1987 = 6%, 1988 to 1993 = 28%). Overall, the survival rate was lower for patients in the expanded ECLS group (59% v 75%; P = .121). When the survival rates for patients supported with ECLS postoperatively were compared for the expanded and early groups, a significant difference (59% v 80%; P < .05) was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of extracorporeal life support in the setting of adult cardiorespiratory failure.

The efficacy of extracorporeal life support (ECLS, ECMO) in the management of severe adult cardiorespiratory failure remains controversial. The purpose of this review is to evaluate the authors' institutional experience with ECLS in adult patients. Between 1988 and 1993, 65 moribund patients with respiratory (n = 51) and cardiac (n = 14) failure were supported with ECLS. Criteria for initiation of ECLS were: 90% chance of mortality despite maximal conventional respiratory management, good potential for recovery, and age younger than 60 years. Venovenous bypass was used in 40 and venoarterial in 25 patients. Respiratory management included low rate, low pressure ventilation with an inspired oxygen fraction < or = 0.5 and tracheostomy tube placement. Continuous systemic heparinization was used, maintaining whole blood activated clotting time (ACT) between 180 and 200 sec. Survival data are summarized as follows: pneumonia (n = 25) 56%, adult respiratory distress syndrome (n = 24) 58%, airway support (n = 2) 100%, and cardiac support (n = 14) 29%. The most common complication was bleeding (68%), which was managed in most patients by reduction of anticoagulation or local measures such as packing. Data from survivors and nonsurvivors of ECLS in patients with respiratory failure were compared in an attempt to define prognostic indicators of improved survival. The only prognostic indicator of survival that could be identified was the period of time on the ventilator before the initiation of ECLS (survivors = 3.0 +/- 2.4 days, nonsurvivors = 6.1 +/9- 4.0 days, P < 0.005). It is concluded that ECLS can be a life saving modality for the management of severe adult cardiorespiratory failure. Earlier institution of ECLS in the course of cardiopulmonary failure may improve outcome.

Extracorporeal life support for adult cardiorespiratory failure.

BACKGROUND: Extracorporeal membrane oxygenation is routinely used for neonatal respiratory failure but is considered unsuccessful in adults based on old studies and old methods. We conducted a new phase 1 trial of modern extracorporeal life support (ECLS) in moribund adults with cardiorespiratory failure. METHODS: Criteria for initiation of ECLS were 90% mortality risk despite maximal conventional care, good potential for recovery, age < 60 years, and no contraindication to anticoagulation. Vascular access for ECLS was performed by operative or percutaneous cannulation. Continuous systemic heparinization was used, maintaining whole blood activated clotting time between 160 to 180 seconds. Blood components were transfused as necessary. Lung management included low rate and low pressure ventilation with an inspired oxygen fraction 0.5 or less. RESULTS: Forty patients were treated with ECLS, 30 with primary respiratory failure and 10 with primary cardiac failure. Twenty-two patients recovered lung or heart function, and 18 patients survived and were discharged from the hospital (14 with respiratory failure and four with cardiac failure, overall survival 45%). The major complication of ECLS was bleeding. CONCLUSIONS: With modern techniques, ECLS can be lifesaving in adult cardiorespiratory failure when conventional therapy has failed.

Neutrophils are not necessary for ischemia-reperfusion lung injury.

The role of neutrophils (PMNs) in ischemia-reperfusion injury after lung transplantation is unclear. If PMNs are involved in ischemia-reperfusion injury in the intact rat, then PMNs should sequester in the injured lung and PMN-depleted rats should develop less injury. Group A rats were treated with a rabbit anti-rat PMN antibody causing profound neutropenia (less than 100 PMNs/microL) and group B with control serum (greater than 2,000 PMNs/microL). Rats were anesthetized and left lung ischemia was sustained for 90 or 180 minutes by clamping the bronchus and the pulmonary artery and vein. Lung injury was quantified by the accumulation of radiolabeled (125I) albumin in ischemic left and nonischemic right lungs (cpm per gram of lung/cpm per gram of blood). Ischemia caused significant lung injury (p less than 0.05) in both PMN-depleted (albumin leak index: 90 min, 0.208; 180 min, 0.218) and nondepleted (90 min, 0.222; 180 min, 0.241) animals compared with nonischemic controls (depleted: 90 min, 0.050; 180 min, 0.100; nondepleted: 90 min, 0.063; 180 min, 0.101); microscopy also demonstrated lung injury. The injury was not associated with PMN sequestration as shown by light microscopy. Thus, we conclude that PMNs are not necessary for ischemia-reperfusion injury and PMN-depletion does not attenuate ischemia-reperfusion injury.

A randomized prospective comparison of MALG with OKT3 for rescue therapy of acute myocardial rejection.

A randomized prospective trial for rescue therapy from acute myocardial rejection was undertaken utilizing Minnesota antilymphoblastic globulin (n = 15) versus murine monoclonal anti-CD3 antibody therapy (OKT3) (n = 14). Patients included in the study had moderate rejection unresponsive to bolus high-dose steroid therapy, or moderate-to-severe rejection with hemodynamic instability. Analysis was performed using the t test and chi-square, significance was P less than 0.05. Patient age, sex, interval from transplant to treatment, and number of unresponsive patients vs. hemodynamically unstable patients were similar in both groups (P greater than 0.05). Initial resolution occurred in 9/15 MALG- vs. 14/14 OKT3-treated patients (P = 0.017). Secondary resolution following repeat treatment occurred in 5/6 remaining MALG patients, for a final resolution of 14/15 MALG vs. 14/14 OKT3 patients (P = NS). Rebound rejection was not significantly different (1/14 MALG vs. 4/13 OKT3). However, 7/14 OKT3-treated patients developed life-threatening infections (1 CMV pancreatitis, 2 CMV pneumonias, 1 systemic candidiasis, 3 CMV viremia) vs. 1/15 MALG-treated patients (CMV viremia) (P = 0.014). Death occurred in 4/14 OKT3- (infection) vs. 1/14 MALG- (rejection) treated patients (P = NS). There were no significant differences in the rate of resolution, rebound, infection, or outcome between unresponsive or hemodynamically unstable patients within either group. Although initial rescue is significantly better with OKT3, final resolution is the same in both groups. Since there was a significant incidence of life-threatening infections (7/14) leading to 4 deaths with OKT3 treatment, we recommend MALG for rescue therapy of refractory acute myocardial rejection if this immunosuppressive regimen is to be used.

Clinical experience with the Nimbus pump.

The Nimbus pump is an indwelling, electromagnetic powered left ventricular (LV) assist device inserted transfemorally. The inflow cannula (7 mm) is positioned across the aortic valve and the pump in the descending aorta. Indications for insertion include cardiogenic shock despite maximal medical support and PCWP greater than 18 mmHg, MAP less than 90 mmHg, and Cl less than 2 L/min/m2. Twelve patients underwent the attempt at surgical insertion of the Nimbus pump. Diagnoses included eight acute myocardial infarctions (AMI), two ischemic cardiomyopathy, one postpartum cardiomyopathy, and one transplanted heart rejection. Eight (67%) of twelve patients had successful insertion. One patient had peripheral vascular disease preventing passage, and three had femoral vessels too small for insertion (less than 7.5 Hagar dilator). Five patients with the diagnosis of AMI had successful insertion and three (60%) underwent sufficient LV recovery for removal of the device; the other two patients died of stroke and ventricular arrhythmias, respectively. Three patients with the diagnosis of cardiomyopathy had progression of the disease process, and their needs exceeded the capabilities of the pump and they died of multiorgan failure. The Nimbus pump is an attractive LV assist device because of its pumping capacity (3.5 L/min) and minor surgical procedure for insertion. However, its application is limited because of access route and size. The device appears to work well for patients in cardiogenic shock after AMI (60% recovery) but does not appear indicated for patients with cadiomyopathy.

Ibuprofen improves survival and neurologic outcome after resuscitation from cardiac arrest.

Post-ischemic inflammatory changes in the central nervous system (CNS) following cardiac arrest and resuscitation are potentially responsible for ultimate survival and much of the neurologic damage, producing greater morbidity and mortality in successfully resuscitated patients. This study was undertaken to assess the non-steroidal anti-inflammatory agent, ibuprofen, in a controlled and monitored experimental model of canine cardiac arrest and resuscitation. With the investigator blinded as to the intervention, eight of 21 dogs were randomly assigned to receive ibuprofen as an i.v. bolus (10 mg/kg) and a 6-h i.v. infusion (5 mg/kg per h). The other 13 dogs received an equivalent volume of 0.9% NaCl to serve as controls. No statistically significant differences between the two groups were detected in any pre-arrest variables. All 21 dogs were successfully resuscitated. At 24 h, dogs receiving ibuprofen exhibited 100% survival, while control dogs exhibited only 54% survival (P = 0.03). The majority of deaths for the control group occurred within the first 6 h. Neurologic deficit scores were assigned at 1, 2, 6 and 24 h after resuscitation. A general trend occurred such that dogs treated with ibuprofen improved over time, while the control dogs remained severely impaired. A significant difference in neurologic deficit score was detected at 6 h (P = 0.01). At 24 h the ibuprofen group exhibited minimal neurologic deficit (5.9 +/- 3.2), and the control group exhibited significantly more severe neurologic impairment (52.2 +/- 13.0, P = 0.01). These results suggest that ibuprofen may be helpful in the pharmacologic management of cardiac arrest as a means of increasing survival and decreasing neurologic impairment.