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Biomedical subjects

Andre C Kalil

Publications and source records attributed to Andre C Kalil.

16 recordsLinked to original sources
PubMed2006

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock.

OBJECTIVE: L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN: Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING: Laboratory. SUBJECTS: Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS: The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS: The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS: These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.

Acetylcysteine↗
PubMed2006

L-Arginine supplementation in sepsis: beneficial or harmful?

PURPOSE OF REVIEW: Recent results are reviewed on the effects of L-arginine supplements in excess of standard nutritional practices during severe sepsis and septic shock. RECENT FINDINGS: Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, a vasoactive product of L-arginine metabolism. L-Arginine has many physiologic and pharmacologic effects that indicate its potential to affect survival in septic patients. Animal studies have documented immunologic effects of L-arginine and of commercial 'immune-enhancing' diets. However, survival studies in small animals have not consistently favored L-arginine. L-Arginine monotherapy in a canine model of septic shock found significant harm at infusion rates of less than twice that administered in standard formulations of total parenteral nutrition. Meanwhile, clinical studies have suffered from lack of statistical power, patient heterogeneity, randomization failures, and use of complex nutritional formulas. Meta-analyses have noted heterogeneity between the effects of immune-enhancing diets in surgical versus medical patients and mixed critically ill populations that include subjects with sepsis, indicating that these results may not be reliably pooled. SUMMARY: To date, published evidence has not established the safety and efficacy of L-arginine at doses above standard dietary practices in severe sepsis or septic shock.

Animals↗
PubMed2005

Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV), the most common opportunistic viral infection in solid organ transplant recipients, is associated with substantial morbidity and mortality. PURPOSE: To assess the efficacy of universal prophylaxis and preemptive approaches in preventing CMV organ disease and other complications in solid organ transplant recipients. DATA SOURCES: Using no language restrictions, the authors searched the following databases from their inception through May 2005: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Evidence-Based Medicine. The authors also reviewed abstracts from scientific meetings and contacted experts and pharmaceutical companies. STUDY SELECTION: Randomized, controlled trials that evaluated antiviral strategies for preventing CMV and associated complications in solid organ transplant recipients were selected. DATA EXTRACTION: Two reviewers independently extracted and assessed the data. DATA SYNTHESIS: The authors found 17 trials involving 1980 patients. Compared with placebo or no therapy, both universal prophylaxis (odds ratio [OR], 0.20 [95% CI, 0.13 to 0.31]) and preemptive strategies (OR, 0.28 [CI, 0.11 to 0.69]) reduced CMV organ disease. However, only universal prophylaxis seemingly reduced CMV organ disease in subgroups of patients at highest risk (donors with positive CMV serostatus and recipients with negative CMV serostatus and induction with antibodies). Both strategies reduced the rate of allograft rejection. Only universal prophylaxis statistically significantly reduced bacterial and fungal infections (OR, 0.49 [CI, 0.36 to 0.67]) and death (OR, 0.62 [CI, 0.40 to 0.96]). Both acyclovir and ganciclovir statistically significantly prevented CMV organ disease in the universal prophylaxis trials. LIMITATIONS: Studies were of modest size, and few studies assessed all outcomes. Studies did not always provide data that discriminated between CMV organ disease and CMV syndrome or data about the timing of CMV organ disease. CONCLUSIONS: Universal prophylaxis and preemptive strategies are beneficial in preventing CMV organ disease in solid organ transplant recipients. Both strategies are associated with a reduction in allograft rejection, but current data suggest that only universal prophylaxis reduces bacterial and fungal infections and death. Acyclovir and ganciclovir are both effective for universal prophylaxis.

Antiviral Agents↗
PubMed2005

Antifungal management practices and evolution of infection in organ transplant recipients with cryptococcus neoformans infection.

BACKGROUND: Therapeutic practices for Cryptococcus neoformans infection in transplant recipients vary, particularly with regards to antifungal agent employed, and duration of therapy. The risk of relapse and time to recurrence is not known. We assessed antifungal treatment practices for cryptococcosis in a cohort of prospectively followed organ transplant recipients. METHODS: The patients comprised 83 transplant recipients with cryptococcosis followed for a median of 2.1 and up to 5.2 years. RESULTS: Patients with central nervous system infection (69% vs. 16%, P = 0.00001), disseminated infection (82.7% vs. 20%, P = 0.00001), and fungemia (29% vs. 8%, P = 0.046) were more likely to receive regimens containing amphotericin B than fluconazole as primary therapy. The use of fluconazole, on the other hand, was more likely for infection limited to the lungs (64% vs. 14%, P = 0.00002). Survival at 6 months tended to be lower in patients whose CSF cultures at 2 weeks were positive compared to those whose CSF cultures were negative (50% vs. 91%, P = 0.06). Maintenance therapy was employed in 68% (54/79) of the patients who survived >3 weeks. The median duration of maintenance therapy was 183 days; 55% received maintenance for > or = 6 months and 25% for >1 year. Relapse was documented in 1.3% (1/79) of the patients. CONCLUSIONS: A majority of the organ transplant recipients with cryptococcosis receive maintenance antifungal therapy for 6 months with low risk of relapse. These data can assist in trials to assess the optimal therapeutic approach and duration of therapy for cryptococcosis in transplant recipients.

Adult↗
PubMed2005

An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients.

BACKGROUND: We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients. METHODS: The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study. RESULTS: In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy. CONCLUSIONS: This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

Adult↗
PubMed2005

Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases.

We describe 2 patients with West Nile virus (WNV) encephalitis who were treated experimentally with interferon (IFN)-alpha. Both patients demonstrated substantial improvement in mentation and speech on the second day of experimental therapy, and neither required endotracheal intubation or admission to the intensive care unit during hospitalization. Moreover, during the 9-month follow-up period, one patient achieved complete recovery, and the other nearly achieved complete resolution of sequelae. To our knowledge, this is the first published report of the use of IFN-alpha to treat WNV encephalitis. Clinical trials are underway to further define the role of this therapy in persons with WNV encephalitis.

Adult↗
PubMed2005

Chicken pox after pediatric liver transplantation.

Previous case series have reported serious complications of chicken pox (CP) after pediatric liver transplantation (PLT), mainly due to visceral dissemination. The goal of our study was to determine the incidence, risk factors, and outcomes of CP after PLT. A case-control study of all CP infections in pediatric transplant recipients followed at our center from September 1993 to April 2004 was performed. Data were collected before and after infection and at the same time points in age-, gender-, and transplant year-matched controls. Potential risk factors prior to CP and adverse outcomes after infection were compared between cases and controls. Twenty (6.2%) developed CP at a median of 1.8 yr (0.6-4.8) after PLT. All CP infections were cutaneous, with no evidence of organ involvement. Twelve were hospitalized: 9 only to receive intravenous acyclovir and 3 stayed > or =2 weeks for other complications. Risk factors were not statistically different among cases and controls. Of the outcomes analyzed, cases were significantly more likely to develop non-CP infections within one year of CP than controls (Hazard Ratio = 12.6, 95% confidence interval = 3.1-51.7; P < 0.001). These infections were often bacterial and occurred long after CP infection. In conclusion, CP is uncommon after PLT and has a low likelihood of organ dissemination. No risk factors were identified. Some cases required prolonged hospitalizations. Close monitoring for the development of late bacterial infections is warranted.

Antibodies, Viral↗
PubMed2004

West Nile virus-associated encephalitis in recipients of renal and pancreas transplants: case series and literature review.

Although West Nile fever is mild in the vast majority of infected persons, there is growing evidence that the disease may be more severe in the immunocompromised population. We describe 3 recipients of kidney or pancreas transplants who developed West Nile fever, 2 of whom had meningoencephalitis. As is the norm when treating serious infections in transplant recipients, a reduction of immunosuppression was pursued for these patients. Despite the severe nature of the disease in 2 patients, all recovered from the disease. The time course of neurologic recovery in the 2 patients with meningoencephalitis is highlighted. We also review the literature on West Nile fever in organ transplant recipients. In areas where West Nile virus is endemic, one must have a high index of suspicion for the illness when dealing with fever in transplant recipients.

Adult↗
PubMed2004

Effects of drotrecogin alfa (activated) in human endotoxemia.

In a phase III clinical trial, drotrecogin alfa (activated) was shown to improve survival and promote faster improvement of cardiovascular and respiratory dysfunction in patients with severe sepsis. To further examine mechanisms involved in the action of this drug, a healthy human endotoxin model was used. Healthy volunteers (eight per group) received drotrecogin alfa (activated) or placebo intravenously for 8 h in a randomized, double-blind, controlled manner. After 2 h of study drug infusion, endotoxin (2 ng/kg) was infused and measurement of physiologic responses and biomarkers continued for 24 h. Consistent with results from severe sepsis clinical trials, drotrecogin alfa (activated) improved mean arterial pressure during the period of infusion after endotoxin exposure. In contrast to severe sepsis clinical trials using drotrecogin alfa (activated) but similar to another human endotoxin study, no significant antithrombotic, profibrinolytic, or anti-inflammatory effects were observed. These results suggest a novel role for drotrecogin alfa (activated) in the human endotoxin model.

Adolescent↗
PubMed2004

Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis.

OBJECTIVE: In a phase 3 trial, recombinant human activated protein C (drotrecogin alfa [activated]) significantly reduced mortality in adult patients with severe sepsis. We have now performed a preliminary analysis of the safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in pediatric patients with severe sepsis. DESIGN AND SETTING: Open-label, nonrandomized, sequential, 2-part study conducted in 11 medical centers in the United States and United Kingdom. PATIENTS: Eighty-three pediatric patients with severe sepsis aged term newborn (>or=38 weeks' gestation) to <18 years old. INTERVENTION: In part 1, drotrecogin alfa (activated) was administered as escalating doses of 6, 12, 24, and 36 micro g/kg per hour for 6 hours for each patient (n = 21). In part 2, drotrecogin alfa (activated) was infused at a rate of 24 micro g/kg per hour for 96 hours in 62 patients. MAIN OUTCOME MEASURES: Plasma clearance, plasma concentration, D-dimer, protein C, and antithrombin levels were measured, and adverse events were monitored. RESULTS: The trial enrolled 83 pediatric patients with severe sepsis, aged term newborn (>or=38 weeks' gestation) to <18 years. In part 1, a dose of 24 micro g/kg per hour produced steady-state plasma concentrations of activated protein C similar to those attained in equivalently dosed adult severe sepsis patients. For all pediatric patients dosed at 24 micro g/kg per hour, the median weight-normalized clearance was 0.45 L/hour/kg and the median steady-state concentration was 51.3 ng/mL. The mean plasma half-life was 30 minutes. Weight-normalized clearance in pediatric and adult patients did not differ significantly with age or weight. D-dimer levels decreased 26% from baseline to end of infusion. Baseline levels of protein C and antithrombin increased 79% and 24%, respectively, over the 96-hour treatment period in part 2. The incidence of serious bleeding during infusion and during the entire study period was 2.4% and 4.8%, respectively. CONCLUSIONS: Pediatric patients with severe sepsis manifest sepsis-induced coagulopathy including protein C deficiency comparable to that seen in adults with severe sepsis. The pharmacokinetics, pharmacodynamic effects, and safety profile of drotrecogin alfa (activated) in pediatric patients are similar to those previously published for adult patients. A large, phase 3, randomized, placebo-controlled study is ongoing to confirm these results and formally assess the safety and efficacy of drotrecogin alfa (activated) in children.

Adolescent↗