Mamdouh Bakhos

Pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting and early tracheal extubation

Numerous clinical studies suggest that methylprednisolone may facilitate early tracheal extubation after cardiac surgery, yet no investigation has rigorously examined the use of the drug in this setting.In this prospective, randomized, double-blind, placebo-controlled study, we examined the pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting (CABG) and early tracheal extubation. Sixty patients undergoing elective CABG and early tracheal extubation were randomized into two groups. Group MP patients received IV methylprednisolone (30 mg/kg during sternotomy and 30 mg/kg during initiation of cardiopulmonary bypass) and Group NS patients received IV placebo at the same two times. Perioperative management was standardized. Alveolar-arterial (A-a) oxygen gradient, lung compliance, shunt, and dead space were determined four times perioperatively. Postoperative tracheal extubation was accomplished at the earliest appropriate time. Both groups exhibited significant postoperative increases in A-a oxygen gradient and shunt (P < 0.000001 for each group) and significant postoperative decreases in dynamic lung compliance (P < 0.000001 for each group). Patients in Group MP exhibited significantly larger increases in postoperative A-a oxygen gradient (P = 0.001) and shunt (P = 0.001) compared with patients in Group NS. Postoperative alterations in dynamic lung compliance, static lung compliance, and dead space were not statistically significant between the groups. The time to postoperative tracheal extubation was prolonged in Group MP patients compared with Group NS patients (769 +/- 294 vs 604 +/- 315 min, respectively; P = 0.05). Methylprednisolone was associated with larger increases in postoperative A-a oxygen gradient and shunt, was unable to prevent postoperative decreases in lung compliance, and prolonged extubation time, which indicate that use of the drug may hinder early tracheal extubation in patients after cardiac surgery. Implications: Traditionally, methylprednisolone has been administered to patients undergoing cardiac surgery to decrease postoperative pulmonary dysfunction. This study revealed that the drug is associated with larger increases in postoperative alveolararterial oxygen gradient and shunt and prolonged tracheal extubation time in patients undergoing coronary artery bypass grafting, which indicate that use of the drug may hinder early tracheal extubation. (Anesth Analg 1998;87:27-33)

Laboratory Diagnosis of Heparin-Induced Thrombocytopenia

The major cause of morbidity and mortality in pa tients with type 1 diabetes mellitus is vascular disease and the death rate in this group of patients can be up to six times that of the general population. Elevated levels of blood glucose can cause endothelial cell damage, and markers of endothelial dam age such as von Willebrand factor (vWF) and thrombomodulin (TM) have been reported to increase in adult diabetic patients. Growth factors are strongly linked to smooth muscle cell pro liferation that contributes significantly to the vascular occlusive process and it has been shown that vascular endothelial cell growth factor (VEGF) stimulates release of vWF from endo thelial cells. Vascular endothelial cell growth factor levels have been shown to be increased in vitreous fluid from the eyes of diabetic patients with proliferative retinopathy compared to those without. In this study we have shown that plasma levels of both TM and VEGF were significantly increased in juvenile diabetic patients with no clinical evidence of vascular disease compared to normal age and sex-matched control subjects. Me dian TM levels were 45.5 ng/mL (I.Q.R. 34 to 56 ng/mL) and 61 ng/mL (I.Q.R. 41 to 72 ng/mL) in the control group and in the diabetic patients respectively (p = .0005) and median lev els of VEGF were 19.6 pg/mL (I.Q.R, 15.9 to 28.1 pg/mL) in the control group and 37.1 pg/mL (I.Q.R. 22.1 to 50.3 pg/mL) in the diabetic patients (p = .027 Mann-Whitney U test). This suggests that microvascular disease begins in childhood and can be detected using laboratory tests before any clinical changes are apparent. Key Words: Diabetes mellitus— Thrombomodulin—Vascular endothelial cell growth factor.

Rivaroxaban - an oral, direct Factor Xa inhibitor - has potential for the management of patients with heparin-induced thrombocytopenia

Rivaroxaban is an oral, direct activated Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Currently available anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs); however, their use can be restricted by heparin‐induced thrombocytopenia (HIT). HIT is usually caused by the production of antibodies to a complex of heparin and platelet factor‐4 (PF4). This study was performed to evaluate, in vitro, the potential of rivaroxaban as an anticoagulant for the management of patients with HIT. UFH, the LMWH enoxaparin, fondaparinux and the direct thrombin inhibitor argatroban were tested to enable comparative analyses. Rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies, unlike UFH and enoxaparin, suggesting that rivaroxaban does not cross‐react with HIT antibodies. Furthermore, rivaroxaban did not cause the release of PF4 from platelets and did not interact with PF4, unlike UFH and enoxaparin. These findings suggest that rivaroxaban may be a suitable anticoagulant for the management of patients with HIT.

Intrathecal morphine for coronary artery bypass graft procedure and early extubation revisited

OBJECTIVE To determine the dose of intrathecal (IT) morphine (along with the intraoperative baseline anesthetic) that provides significant analgesia yet does not delay extubation in the immediate postoperative period in patients undergoing cardiac surgery and early extubation. DESIGN Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING Single university hospital. PARTICIPANTS Forty patients undergoing elective coronary artery bypass graft procedure and early extubation. INTERVENTIONS Twenty patients received 10 microg/kg of IT morphine, and 20 patients received IT placebo. Perioperative anesthetic management was standardized and included postoperative patient-controlled morphine analgesia. MAIN RESULTS Of the patients tracheally extubated during the immediate postoperative period, mean time to extubation was similar in patients who received IT morphine (6.8+/-2.8 h) or IT placebo (6.5+/-3.2 h). Four patients who received IT morphine had extubation substantially delayed because of prolonged ventilatory depression. There was no difference between groups in postoperative patient-controlled morphine analgesia use. CONCLUSION Even when used in conjunction with an intraoperative baseline anesthetic that allows early extubation, IT morphine (10 microg/kg) was unable to provide substantial postoperative analgesia. The risks of using IT morphine in patients undergoing cardiac surgery and early extubation may outweigh the potential benefits.

Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation

BACKGROUND Whether or not methylprednisolone is beneficial during cardiac operation remains controversial. This study examines the effects of the drug on complement activation and hemodynamics in patients undergoing cardiac operation and early extubation. METHODS Patients undergoing cardiac operation were randomized to receive either intravenous methylprednisolone (group MP) or intravenous placebo (group NS). Complement 3a (C3a) levels and hemodynamic parameters were obtained perioperatively. Extubation was accomplished at the earliest clinically appropriate time. RESULTS Both groups exhibited equivalent increases in C3a levels after exposure to bypass. Group MP exhibited increased cardiac index, decreased systemic vascular resistance, and increased shunt flow when compared to group NS. More group MP patients required hemodynamic support and group MP patients had prolonged extubation times. CONCLUSIONS Methylprednisolone was unable to attenuate complement activation and led to hemodynamic alterations (primarily vasodilation) that may hinder early extubation in patients after cardiac operations.

POTENTIAL USE OF RECOMBINANT HIRUDIN AS AN ANTICOAGULANT IN A CARDIOPULMONARY BYPASS MODEL

Recombinant (r) hirudin is a potent thrombin-specific inhibitor derived from the natural hirudin of the leech (Hirudo medicinalis). We have studied the efficacy of r-hirudin compared with heparin in a canine model of cardiopulmonary bypass operations. Two administration regimens were used for r-hirudin: group 1, 1.0 mg/kg intracardiac bolus then intravenous bolus at 30 minutes (n = 10); and group 2, 1.0 mg/kg intracardiac bolus with 1.25 +/- 0.04 mg.kg-1.h-1 intravenous infusion (n = 8). Group 3 was given an intracardiac bolus of heparin, 1.66 mg/kg (n = 9). Aspiration of blood from the chest cavity revealed no significant difference between the three groups. Measurement of fibrin deposits in the pump line filter revealed higher amounts in the r-hirudin groups (p = 0.02). Decreases in platelets, fibrinogen, and hematocrit due primarily to hemodilution were the same in each group. The bleeding time assay showed less prolongation for r-hirudin than for heparin (p less than 0.001). No antagonist for r-hirudin was used; however, due to its short half-life all coagulation variables returned to baseline within 30 minutes after cardiopulmonary bypass. Because r-hirudin lacks effect on platelets, is a poor immunogen, does not require a plasma cofactor, and may not require an antagonist, it may provide an alternative anticoagulant to heparin in cardiopulmonary bypass. Additional studies are, however, needed to optimize the dose and to evaluate other clinical aspects of r-hirudin.

Refractory post-transplant airway strictures: successful management with wire stents

OBJECTIVE Bronchial stenosis, malacia and dehiscence are major airway complications of lung transplantation. Our success in managing this problem evolved from the use of semi-rigid dilators, to balloon dilation and placement of a stent, which were initially silicone, thereafter wire balloon-expandable and finally wire self-expandable. METHODS From May, 1994 until July 1997, we performed a total of 49 single and 58 bilateral lung transplants. Symptoms of shortness of breath, verified by a drop in the forced expiratory volume in one second (FEV1), led to bronchoscopic inspection of the airway in lung transplant patients. Eighteen patients (16%) suffered a severe form of airway complication (dehiscence or stenosis) in 24 of 151 airways at risk (15.9%). These anastomotic strictures were recalcitrant to conventional therapy. Intervention consisted of rigid bronchoscopy, dilation of the stricture and placement of a stent. Flexible bronchoscopy and fluoroscopy were used for precise placement of the stent. As the initial stent, the Hood silicone stent was placed five times in four patients and the Dumont studded stent five times in four patients. The Palmaz wire stent was used as the initial stent 10 times in seven patients and the Wallstent used eight times in seven patients. Four patients had multiple stents. Balloon inflation moulded the wire stent to the airway. RESULTS There was no mortality resulting from the airway complication or any intervention. The most serious complication was a perforation of the airway using the semi-rigid dilator that necessitated immediate thoracotomy and re-anastomosis of the bronchus. Other complications necessitated repeat interventions due to restenosis or failure of the stents. The success of the stent placement was measured subjectively by the immediate ease of breathing enjoyed by each patient and objectively by the significant increase of the FEV1 from a pre-operative mean of 1.19 l (SD 0.64 l) to a post-operative mean of 2.06 l (SD 0.70 l) (P < 0001). The mean number of interventions according to the type of wire stent first used was significantly fewer with Wallstent insertion (1.28 (SD 0.48)) than in those patients in whom a Palmaz stent was inserted (5.22 (SD 2.38)) (P < 0008). CONCLUSION The airway complication of stricture, broncho-malacia or dehiscence following lung transplantation can be managed effectively and easily with the use of balloon catheter dilation followed by precise placement of a self-expandable wire stent. The Wallstent is the superior stent for this application.

Ventricular aneurysm due to blunt chest injury

A left ventricular aneurysm developed in 3 patients sustaining blunt chest injury. Evidence of an acute myocardial infarction on the electrocardiogram and enzyme analysis prompted cardiac catheterization, which revealed total occlusion of the left anterior descending coronary artery in 2 of the 3 patients. Ventricular aneurysmectomy was performed in each patient. A review of the literature revealed 32 previously reported patients with left ventricular aneurysm caused by blunt trauma. Clinical features, catheterization or autopsy findings, and outcome are examined.

Differentiating Low-Molecular-Weight Heparins Based on Chemical, Biological, and Pharmacologic Properties : Implications for the Development of Generic Versions of Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

Qualitative evaluation of coronary flow during anesthetic induction using thallium-201 perfusion scans.

Qualitative distribution of coronary flow using thallium-201 perfusion scans immediately postintubation was studied in 22 patients scheduled for elective coronary artery bypass surgery. Ten patients received a thiopental (4 mg/kg) and halothane induction. Twelve patients received a fentanyl (100 μg/kg) induction. Baseline thallium-201 perfusion scans were performed 24 h prior to surgery. These scans were compared with the scans performed postintubation. A thallium-positive scan was accepted as evidence of relative hypo-perfusion. Baseline hemodynamic and ECG data were obtained prior to induction of anesthesia. These data were compared with the data obtained postintubation. Ten patients developed postintubation thallium-perfusion scan defects (thallium-positive scan), even though there was no statistical difference between their baseline hemodynamics and hemodynamics at the time of intubation. There was no difference in the incidence of thallium-positive scans between those patients anesthetized by fentanyl and those patients anesthetized with thiopental-halothane. The authors conclude that relative hypoperfusion, and possibly ischemia, occurred in 45% of patients studied, despite stable hemodynamics, and that the incidence of these events was the same with two different anesthetic techniques.