Combination Drug Products for HIV—A Word of Caution for the Transplant Clinician

Modern‐day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed‐dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV‐infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction–induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat‐containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV‐positive transplant recipients and their providers.     

Umbilical Negative Pressure Dressing for Transumbilical Appendectomy in Childern

Methods:This study was a retrospective chart review of 1377 patients (2–20 years) undergoing laparoscopic appendectomy for acute appendicitis in 2 tertiary care referral centers from January 2007 through December 2012. Twenty-two different operative technique/dressing variations were documented. The 6 technique/dressing groups with >50 patients were assessed, including a total of 1283 patients.Results:The surgical site infection rate of the 220 patients treated with TULAA and application of an umbilical vacuum dressing with dry gauze is 1.8% (95% CI, 0.0–10.3%). This compares to an infection rate of 4.1% (95% CI, 1.3–10.5%) in 97 patients with dry dressing without vacuum. In the 395 patients who received an umbilical vacuum dressing with gauze and bacitracin, the surgical site infection rate was found to be 4.3% (95% CI, 2.7–6.8%).Conclusions:Application of an umbilical negative-pressure dressing with dry gauze lowers the rate of umbilical site infections in patients undergoing transumbilical laparoscopic-assisted appendectomy for acute appendicitis.     

Is repeated head computed tomography necessary for traumatic intracranial hemorrhage?

This study was performed to determine the need for repeat head computed tomography (CT) in patients with blunt traumatic intracranial hemorrhage (ICH) who were initially treated nonoperatively and to determine which factors predicted observation failure or success. A total of 1,462 patients were admitted to our level II trauma center for treatment of head injury. Seventeen per cent (255/1,462) were diagnosed with ICH on initial head CT. Craniotomy was initially performed in 15.7 per cent (40/255) of patients with ICH. Two hundred sixteen patients with ICH were initially observed. Ninety-seven per cent (179/184) of observed patients with ICH and repeat head CT never underwent a craniotomy, 2.7 per cent (5/184) of patients with ICH initially observed underwent craniotomy after repeat head CT, and four patients (80%) had deteriorating neurologic status. Multivariate analysis revealed the following significant admission risk factors were associated with a need for repeat head CT indicating the need for craniotomy: treatment with anticoagulation and/or antiplatelet medications, elevated prothrombin time (PT), and age greater than 70 years. In patients with blunt traumatic intracranial hemorrhage initially observed, there is little utility of repeated head CT in the absence of deteriorating neurologic status. The only admission risk factors for a repeat CT indicating the need for craniotomy were advanced age and coagulopathy.     

A multidisciplinary protocol improves electrolyte replacement and its effectiveness

Background

We implemented a multidisciplinary electrolyte replacement protocol in a tertiary referral center surgical intensive care unit. The purpose of this study was to evaluate its efficacy.

Methods

This was a retrospective study. The electrolyte replacement protocol was designed for the replacement of potassium, magnesium, and phosphorous and was nurse driven. Data evaluated included patient demographics and details specific to electrolyte replacement. Univariate analyses were performed by using the Student t test and the Fisher exact test. A P value of <.05 was considered significant.

Results

After implementation of the protocol, overall electrolyte replacement improved from 70% to 79% (P = .03), and its overall effectiveness increased from 50% to 65% (P = .01). Individual electrolyte replacement, effectiveness, and dosing varied.

Conclusions

The implementation of a multidisciplinary electrolyte replacement protocol in a tertiary referral center surgical intensive care unit significantly improved both overall electrolyte replacement and its effectiveness.     

Whole-body MRI for the detection of bone marrow involvement in lymphoma: prospective study in 116 patients and comparison with FDG-PET

Objective

To assess and compare the value of whole-body MRI with FDG-PET for detecting bone marrow involvement in lymphoma.

Methods

A total of 116 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI and blind bone marrow biopsy (BMB) of the posterior iliac crest. Of 116 patients, 80 also underwent FDG-PET. Patient-based sensitivities of whole-body MRI for detecting bone marrow involvement were calculated using BMB as reference standard and compared with FDG-PET in aggressive and indolent lymphomas separately.

Results

Sensitivity of whole-body MRI in all lymphomas was 45.5 % [95 % confidence interval (CI): 29.8–62.0 %]. Sensitivity of whole-body MRI in aggressive lymphoma [88.9 % (95 % CI: 54.3–100 %)] was significantly higher (P?=?0.0029) than that in indolent lymphoma [23.5 % (95 % CI: 9.1–47.8 %)]. Sensitivity of FDG-PET in aggressive lymphoma [83.3 % (95 % CI: 41.8–98.9 %)] was also significantly higher (P?=?0.026) than that in indolent lymphoma [12.5 % (95 % CI: 0–49.2 %)]. There were no significant differences in sensitivity between whole-body MRI and FDG-PET (P?=?1.00)

Conclusion

Sensitivity of whole-body MRI for detecting lymphomatous bone marrow involvement is too low to (partially) replace BMB. Sensitivity of whole-body MRI is significantly higher in aggressive lymphoma than in indolent lymphoma and is equal to FDG-PET in both entities.

Key Points

? Bone marrow involvement in lymphoma has prognostic and therapeutic implications. ? Blind bone marrow biopsy (BMB) is standard for bone marrow assessment. ? Neither whole-body MRI nor FDG-PET can yet replace BMB. ? Both techniques have higher sensitivity in aggressive than in indolent lymphoma. ? Both imaging techniques are complementary to BMB.     

Induction of necrosis and DNA fragmentation during hypothermic preservation of hepatocytes in UW,HTK, and Celsior solutions

Donor cells can be preserved in University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK), or Celsior solution. However, differences in efficacy and mode of action in preventing hypothermia-induced cell injury have not been unequivocally clarified. Therefore, we investigated and compared necrotic and apoptotic cell death of freshly isolated primary porcine hepatocytes after hypothermic preservation in UW, HTK, and Celsior solutions and subsequent normothermic culturing. Hepatocytes were isolated from porcine livers, divided in fractions, and hypothermically (4 degrees C) stored in phosphate-buffered saline (PBS), UW, HTK, or Celsior solution. Cell necrosis and apoptosis were assessed after 24- and 48-h hypothermic storage and after 24-h normothermic culturing following the hypothermic preservation periods. Necrosis was assessed by trypan blue exclusion, lactate dehydrogenase (LDH) release, and mitochondrial 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. Apoptosis was assessed by the induction of histone-associated DNA fragments and cellular caspase-3 activity. Trypan blue exclusion, LDH release, and MTT reduction of hypothermically preserved hepatocytes showed a decrease in cell viability of more than 50% during the first 24 h of hypothermic preservation. Cell viability was further decreased after 48-h preservation. DNA fragmentation was slightly enhanced in hepatocytes after preservation in all solutions, but caspase-3 activity was not significantly increased in these cells. Normothermic culturing of hypothermically preserved cells further decreased cell viability as assessed by LDH release and MTT reduction. Normothermic culturing of hypothermically preserved hepatocytes induced DNA fragmentation, but caspase-3 activity was not hanced in these cells. Trypan blue exclusion, LDH leakage, and MTT reduction demonstrated the highest cell viability after storage in Celsior, and DNA fragmentation was the lowest in cells that had been stored in PBS and UW solutions. None of the preservation solutions tested in this study was capable of adequately preventing cell death of isolated porcine hepatocytes after 24-h hypothermic preservation and subsequent 24-h normothermic culturing. Culturing of isolated and hypothermically preserved hepatocytes induces DNA fragmentation, but does not lead to caspase-3 activation. With respect to necrosis and DNA fragmentation of hypothermically preserved cells, UW and Celsior were superior to PBS and HTK solutions in this model of isolated porcine hepatocyte preservation.     

Thymoglobulin,sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation

BACKGROUND: We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection. METHODS: A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL. RESULTS: The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5+/-1 (mean+/-standard deviation). With a mean follow-up of 13.6+/-4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9+/-3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2+/-0.3 mg/dL, fasting glucose was 88+/-15 mg/dL, and sirolimus dose at month 3 was 6.3+/-3 mg per day and at month 12 2.7+/-1 mg per day. The average total daily cyclosporine A dose at month 3 was 208+/-62 mg per day and 133+/-13 mg per day at 1 year. CONCLUSIONS: This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.     

Evaluation of 4-mm to 7-mm versus 6-mm prosthetic brachial-antecubital forearm loop access for hemodialysis: results of a randomized multicenter clinical trial

OBJECTIVE: Prosthetic arteriovenous fistulas for hemodialysis vascular access have a high incidence rate of thrombotic occlusions that result in graft failure. This randomized multicenter study was performed to assess the patency rates and the effect of 4-mm to 7-mm grafts on the development of stenoses. METHODS: A total of 109 patients who needed vascular access for hemodialysis were randomized to receive either 6-mm (n = 57) or 4-mm to 7-mm prosthetic brachial-antecubital forearm loop accesses (polytetrafluoroethylene). Duplex scanning, with measurement of blood flow and peak systolic velocity and detection of stenoses (>50%), was performed at 1, 6, and 12 months after surgery. Clinical data were obtained in a prospective manner and primary, assisted primary, and secondary patency rates were calculated with the Kaplan-Meier life-table analysis. Statistical analysis was performed with the independent samples t test and chi(2) test. RESULTS: At 1 year, patency rates were similar for both 4-mm to 7-mm and 6-mm prostheses (primary, 46% versus 43%; assisted primary, 62% versus 58%; secondary, 87% versus 91%). The incidence rate of thrombotic occlusion was comparable for both groups (0.74/patient-year versus 0.88/patient-year; P >.05). Mean graft flow at 1, 6, and 12 months was 1416 versus 1415 mL/min, 1345 versus 1319 mL/min, and 1595 versus 1265 mL/min (P >.05) for 4-mm to 7-mm and 6-mm grafts, respectively. Also, no differences in peak systolic velocities in any part of the grafts were observed. The percentage of stenoses detected was equal in both groups at 1 year after surgery (27% versus 20%; P >.05). CONCLUSION: A 4-mm to 7-mm tapered prosthetic brachial-antecubital forearm loop access did not reduce the incidence rates of stenoses and thrombotic occlusions compared with a 6-mm prosthetic conduit. Moreover, no differences in patency rates were observed. Therefore, we believe that the 4-mm to 7-mm graft should not be used routinely for hemodialysis vascular access.     

Unusual absence of endothelium-dependent or -independent vasodilatation to purines or pyrimidines in the rat renal artery

BACKGROUND: Adenosine triphosphate (ATP) is a cotransmitter with noradrenaline (NA) in sympathetic perivascular nerves. It has a dual role in the maintenance of vascular tone as ATP, released from endothelial cells during shear stress or hypoxia, induces vasodilatation via endothelial P2Y receptors or by direct action on smooth muscle. The role and distribution of P2 receptors is well characterized for many blood vessels but not for the rat renal artery. This study aims to determine whether ATP is a vasoconstrictor cotransmitter with NA and whether ATP induces vasodilatation via the endothelium or smooth muscle. METHODS: On isolated rat renal arteries, electrical field stimulation (EFS) in the absence and presence of antagonists to P2X receptors and alpha1-adrenoceptors was examined. Concentration-response curves were constructed to NA, ATP, alpha,beta-methylene ATP (alpha,beta-meATP), uridine triphosphate (UTP), and 2-methylthio ADP (2-MeSADP) on low tone. Curves to acetylcholine (ACh), 2-MeSADP, and UTP were constructed on raised tone. Immunofluorescent localization of P2X and P2Y receptor subtypes was performed. RESULTS: Electrical field stimulation induced vasoconstriction, partially inhibited by the P2X receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, and predominantly by prazosin. Exogenous NA and ATP mimicked EFS; immunostaining for P2X1 and P2X2 receptors was expressed on vascular smooth muscle. Unusually, ATP, 2-MeSADP, and UTP failed to induce vasodilatation. Acetylcholine induced vasodilatation. alpha,beta-meATP, 2-MeSADP, and UTP induced vasoconstriction via P2X1, P2Y1, and P2Y2 receptors, respectively. Immunostaining for P2X1, P2Y1, and P2Y2 receptors was expressed on the vascular smooth muscle. CONCLUSION: Adenosine triphosphate and NA are cotransmitters in sympathetic nerves supplying the rat renal artery, NA being the dominant partner. The novel feature of this vessel is that purines and pyrimidines do not produce either endothelium-dependent or -independent vasodilatation; P2X1, P2Y1, and P2Y2 receptors on the smooth muscle all mediate vasoconstriction.