Oliver Thomusch

Validity of intra-operative neuromonitoring signals in thyroid surgery

BackgroundAlthough intra-operative neuromonitoring (IONM) is widely used in thyroid surgery, the validity of the received IONM signals are still unknown.MethodProspective collection of data forms in 29 hospitals from 8,534 patients with 15,403 nerves at risk, who underwent surgery for benign and malignant goitre disorders between August 1999 and January 2001. IONM was performed by indirect stimulation via the vagal nerve and by direct recurrent laryngeal nerve (RLN) stimulation in 12,486 cases. IONM signals were compared with early (<14 days) and late (6 months) postoperative vocal cord function findings.ResultsThe transient and permanent RLN palsy rate was 2.8% and 0.7%, respectively. Monitoring of the RLN function was significantly more reliable via the indirect IONM stimulation route than via the direct IONM stimulation route (specificity P<0.05). IONM by indirect stimulation via the vagal nerve reliably excluded postoperative, permanent, vocal cord palsy (specificity 97.6%, negative predictive value 99.6%). However, a changed IONM was insufficient to predict permanent RLN palsy (sensitivity 45.9%, positive predictive value 11.6%). IONM was not associated with increased general morbidity.ConclusionsFor intra-operative neuromonitoring, indirect stimulation of the RLN is superior to direct stimulation. An intact acoustic IONM signal is highly predictive of intact postoperative RLN function. When the IONM signal is abnormal or absent, a one-stage extensive thyroid resection should be performed only if the surgeon is absolutely convinced that the first RLN is not harmed or a total thyroidectomy is mandatory.

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial

BACKGROUND Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING Johnson & Johnson Medical Limited.

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial

BACKGROUND Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. METHODS In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. FINDINGS Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. INTERPRETATION Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. FUNDING Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Twenty-year graft survival and graft function analysis by a matched pair study between pediatric en bloc kidney and deceased adult donors grafts.

Background. Pediatric en bloc kidney grafts, especially those from donors aged younger than 12 months, are still regarded controversially with respect to long-term graft survival and function as well as the postoperative development of serious hypertension and proteinuria. Patients and Methods. This retrospective single-center study analyzed 78 pediatric en bloc kidney grafts transplanted between October 1989 and December 2008. Mean donor age was 15 months in the pediatric en bloc kidney donor group and 37.8 years in the matched pair group. The mean follow-up period was 9.3 years (range, 1-19 years). Statistical analysis was performed using the Kaplan-Meier test for patient and graft survival. Continuous variables were compared using independent sample t test. Results. Graft survival for the pediatric donors after 1, 5, and 10 years were 83.1%, 76.0%, 73.9% and for the matched pair control group 89.6%, 78.7%, and 57.8%, respectively. Serum creatinine levels after 1, 5, and 10 years were 1.0, 0.8, 1.1 mg/dL and for the matched pair control group 1.5, 1.7, and 1.6 mg/dL, respectively. No significant long-term differences were detected between the study cohort groups with respect to the postoperative development of hypertension and proteinuria. Conclusion. Overall, pediatric en bloc kidney grafts are well suited to extend the scarce kidney donor pool in experienced centers because of a superior long-term outcome for graft survival and function in comparison with deceased adult kidney grafts. Special attention has to be paid to the substantial higher initial graft loss rate during the first postoperative year.

The genetic predisposition of natural killer cell to BK virus-associated nephropathy in renal transplant patients

BK virus (BKV) infection represents a serious complication in renal transplant patients resulting in BKV-associated nephropathy and subsequent allograft loss. Natural killer cells are crucial in the antiviral immune response; however, an understanding of the role of natural killer cells in protection against BKV is limited. To elucidate whether killer-cell immunoglobulin-like receptors and their interaction between donor-/recipient-related ligands have a role in BKV infection, we performed genotyping analysis in 48 kidney transplant recipients with a history of severe BKV infection/BKV-associated nephropathy and 110 recipients with stable renal function and no BKV reactivation. Of interest, we found that telomeric gene content motif was significantly associated with severe course of BKV infection/BKV-associated nephropathy and detected significantly higher percentage of patients with BKV-associated nephropathy carrying low numbers of activating receptors compared with the control group. Detailed analysis of each single receptor revealed significantly lower frequencies of the activating receptor KIR3DS1 in patients with BKV infection/nephropathy as compared with the controls. Thus, our study supports protective effects of activating receptors in BKV infection and suggest natural killer-cell-related genetic predisposition to the development of BKV-associated nephropathy.

Targeting vascular endothelial growth factor pathway offers new possibilities to counteract microvascular disturbances during ischemia/reperfusion of the pancreas.

Background. It is of crucial importance to explore new therapeutic strategies capable of combating or even preventing pancreatic graft failure after transplantation caused by ischemia reperfusion damage. So far, the role of the hypoxia induced mediator vascular endothelial growth factor (VEGF) upon pancreatic microcirculation has not been described. Therefore the aim of this study was to investigate its influence, using the novel tyrosinekinase inhibitor PTK787/ZK222584 (PTK/ZK), upon functional capillary density (FCD), leukocyte-endothelium interaction (LEI), and macromolecular permeability (P) of normal and postischemic pancreas tissue. Methods. Sprague-Dawley rats were anesthetized and randomly assigned to five groups (n=7/group): (a) sham, (b) ischemia/reperfusion (I/R) control, (c) I/R and PTK/ZK treatment, (d) VEGF-superfusion, (e) VEGF-superfusion and PTK/ZK-treatment. A recently established method of digital dynamic intravital epifluorescence microscopy was used for evaluating the effective microvascular permeability together with FCD and LEI. Results. Comparison between sham vs. I/R shows a significant upregulation of VEGF-expression followed by deterioration of microcirculation with decreased FCD, increased P and LEI. Treatment with PTK/ZK resulted in a significant decrease of P under conditions of superfusion with VEGF as well as I/R compared to corresponding groups without treatment. Conclusion. VEGF plays a crucial causative role involving an increase in permeability in normal as well as in postischemic pancreatitis via tyrosinkinase receptors. VEGF seems to be partly accountable for a deterioration of FCD and an upregulation of LEI via VEGF-tyrosinekinase receptor independent mechanisms. VEGF might be a promising potential therapeutic target in order to minimize edema formation caused by I/R and pancreatitis in pancreas transplantation.

Kidney transplantation with concomitant unilateral nephrectomy: a matched-pair analysis on complications and outcome.

Background. We sought to determine the impact of kidney transplantation with simultaneous unilateral nephrectomy on perioperative morbidity and patient and graft survival. Methods. From January 1990 to May 2004, 75 kidney transplantations with simultaneous unilateral nephrectomy (group NE+) were performed at the University of Freiburg. Of these, 49 had polycystic kidney disease. Patients of group NE+ were matched with 75 kidney transplants without nephrectomy (group NE−). Immunosuppressive maintenance therapy in both groups was based on cyclosporineA, mycophenolate mofetil or azathioprine, and prednisone. Mean follow up was 4.1 yrs (range 0.3–11.7 yrs). Results. Patient survival rate at 1 and 5 yrs was 95% and 84% versus 95% and 93% in group NE+ and NE−, resp. (P=0.56). Accordingly, kidney function rate was 85% and 74% in group NE+ versus 89% and 79% in group NE− (P=0.89). Perioperative (90 days) mortality rate in group NE+ was 1.3% and 2.7% in group NE− (P=0.56). Perioperative surgical complications were similar in both groups. Conclusions. Kidney transplantation with concomitant unilateral nephrectomy has no negative impact on patient or graft survival and is associated with a reasonable morbidity rate.

Protective role of heme oxygenase-1 in pancreatic microcirculatory dysfunction after ischemia/reperfusion in rats.

Objectives: Microcirculatory derangements caused by ischemia and reperfusion (I/R) play a pivotal role in acute and graft pancreatitis. The inducible enzyme heme oxygenase 1 (HO-1) has been shown to decrease I/R injury by modulation of capillary perfusion in other organs. It was the aim of this study to evaluate the effect of HO-1 induction on pancreatic microcirculation after I/R. Methods: Rats were randomized into 4 groups: (1) sham controls; (2) 1-hour ischemia and 2-hour reperfusion (I/R); (3) I/R + cobalt protoporphyrin (CoPP), an HO-1 inducer; and (4) I/R + CoPP + tin protoporphyrin, an HO inhibitor. Functional capillary density (FCD) and leukocyte endothelium interaction were analyzed using intravital microscopy during reperfusion. Expression of HO-1 mRNA, HO-1 protein, and HO activity were assessed by Northern blot, Western blot, and an HO activity assay. Results: Functional capillary density decreased significantly in the I/R group as compared with sham controls. Cobalt protoporphyrin treatment increased FCD to control values. In contrast, HO inhibition in CoPP-pretreated animals lowered FCD and increased leukocyte endothelium interaction significantly. Cobalt protoporphyrin administration increased HO-1 mRNA, protein, and HO activity, whereas activity of the enzyme was reduced after injection of tin protoporphyrin. Conclusions: Heme oxygenase 1 plays a beneficial role in pancreatic microcirculatory derangements after I/R. This could be of therapeutic relevance after pancreas transplantation and other forms of postischemic pancreatitis.

Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re-transplantation

AIM To determine the impact of transplant nephrectomy on peak panel reactive antibody (PRA) levels, patient and graft survival in kidney re-transplants. METHODS From 1969 to 2006, a total of 609 kidney re-transplantations were performed at the University of Freiburg and the Campus Benjamin Franklin of the University of Berlin. Patients with PRA levels above (5%) before first kidney transplantation were excluded from further analysis (n = 304). Patients with graft nephrectomy (n = 245, NE+) were retrospectively compared to 60 kidney re-transplants without prior graft nephrectomy (NE-). RESULTS Peak PRA levels between the first and the second transplantation were higher in patients undergoing graft nephrectomy (P = 0.098), whereas the last PRA levels before the second kidney transplantation did not differ between the groups. Age adjusted survival for the second kidney graft, censored for death with functioning graft, were comparable in both groups. Waiting time between first and second transplantation did not influence the graft survival significantly in the group that underwent nephrectomy. In contrast, patients without nephrectomy experienced better graft survival rates when re-transplantation was performed within one year after graft loss (P = 0.033). Age adjusted patient survival rates at 1 and 5 years were 94.1% and 86.3% vs 83.1% and 75.4% group NE+ and NE-, respectively (P < 0.01). CONCLUSION Transplant nephrectomy leads to a temporary increase in PRA levels that normalize before kidney re-transplantation. In patients without nephrectomy of a non-viable kidney graft timing of re-transplantation significantly influences graft survival after a second transplantation. Most importantly, transplant nephrectomy is associated with a significantly longer patient survival.

Successful Transplantation of Kidneys from a Donor with Myoglobinuric Acute Renal Failure

The shortage of donor organs is reflected in the growing number of patients on the waiting list for kidney transplantation worldwide. It seems to be sensible to expand the scarce donor pool by the cautious use of extended donor criteria. Kidneys from a 21‐year‐old deceased donor road traffic accident victim who suffered acute renal failure (ARF) due to myolysis were transplanted. Both transplantations were successful after an initial period of delayed graft function. Therefore, kidneys from deceased donors with ARF should not be excluded for transplantation in general.