Goal-Directed Haemodynamic Therapy Improves Patient Outcomes in Kidney Transplantation.

Introduction: Kidney transplant graft function depends on optimised haemodynamics. However, high fluid volumes risk hypervolaemic complications. The Edwards Lifesciences ClearSight™ device permits fluid titration through markers of preload and beat-to-beat blood pressure monitoring. We evaluated the implementation of a novel goal-directed haemodynamic therapy protocol to determine whether patient outcomes had improved. Design: A retrospective evaluation of standard care versus goal-directed haemodynamic therapy in adults undergoing kidney transplantation was performed in a single centre between April 2016 and October 2019. Twenty-eight standard-of-care patients received intraoperative fixed-rate infusion and 28 patients received goal-directed haemodynamic therapy. The primary outcome was volume of fluid administered intraoperatively. Secondary outcomes included blood product and vasoactive drug exposure, graft and recipient outcomes. Results: Intraoperative fluid administered was significantly reduced in the goal-directed haemodynamic therapy cohort (4325 vs 2751 ml, P < .001). Exposure to vasopressor (67.9% vs 42.9%, P = .060) and blood products (17.9% vs 3.6%, P = .101) was unchanged. Immediate graft function (82.1% vs 75.0%, P = .515), dialysis requirement (14.3% vs 21.4%, P = .729) and creatinine changes post-operatively were unchanged. In the goal-directed haemodynamic therapy cohort, 1 patient had pulmonary oedema (3.6%) versus 21.4% in the standard cohort. Patients in the goal-directed haemodynamic therapy group were more likely to mobilise within 48 hours of surgery (number needed to treat = 3.5, P = .012). Conclusions: Protocolised goal-directed haemodynamic therapy in kidney transplantation was safe and may improve patient, graft, and surgical outcomes. Clinical trials assessing goal-directed approaches are needed.

Not All Piggybacks Are Equal: A Retrospective Cohort Analysis of Variation in Anhepatic Transcaval Pressure Gradient and Acute Kidney Injury During Liver Transplant.

OBJECTIVES: Complete inferior vena cava clamping in cavalreplacement during livertransplantis associated with substantial physiological derangement and postoperative morbidity. Partial clamping in the piggyback technique may be relatively protective, but evidence is lacking. Having observed substantial variation in transhepatic inferior vena cava pressure gradient with piggyback, we hypothesized that the causative mechanism is the extent of caval clamping rather than the surgical approach. MATERIALS AND METHODS: We used internal jugular and femoral catheters to estimate suprahepatic and infrahepatic inferior vena cava pressures during clamping. Pressure gradients were calculated, and distributions were compared by surgical technique. We estimated adjusted odds ratios for pressure gradient on acute kidney injury at 72 hours. RESULTS: In 115 case records, we observed substantial variation in maximum pressure gradient; median values were 18.0 mm Hg(interquartile range, 8.0-25.0 mm Hg) with the piggyback technique and 24.0 mm Hg (interquartile range, 19.5-27.0 mm Hg) with caval replacement. Incidence of acute kidney injury was 25% (29 patients). Pressure gradient was linearly associated with probability of acute kidney injury (odds ratio, 1.06; 95% CI, 1.01-1.13). CONCLUSIONS: We report 2 novel findings. (1) Anhepatic inferior vena cavapressuregradient variedsubstantially in individuals undergoing piggyback, and (2) gradient was positively associatedwith early acute kidney injury. We hypothesize that this (unmeasured) variation explains the conflictingfindings ofprevious studies that compared surgical techniques. Also, we propose that caval pressure gradient could be routinely assessed to optimize real-time piggyback clamp position during livertransplant surgery.

Association Between Fast-Track Extubation After Orthotopic Liver Transplant, Postoperative Vasopressor Requirement, and Acute Kidney Injury.

OBJECTIVES: Acute kidney injury is a significant cause of morbidity after orthotopic liver transplant. Early extubation after liver transplant may have a beneficial effect on postoperative renal function. This may be the result of reduction in vasopressor-mediated vasoconstriction used to counteract the hypotension associated with sedative use and the effects of positive-pressure ventilation. Previous studies explored advantages of early extubation after liver transplant but focused on resource usage rather than clinical benefit. This study was designed to determine the association between fast-track extubation and reduction in postoperative vasopressor requirement and whether this had any association with acute kidney injury incidence or renal replacement therapy requirement. MATERIALS AND METHODS: Data were collected from 144 orthotopic liver transplants. A propensity-matched case-control analysis was conducted on a subgroup of 33 patients who were fast-track extubated and with 33 propensity score-matched control patients who were not. The primary outcome was median days of postoperative vasopressor use, and secondary outcomes included incidence of acute kidney injury, renal replacement therapy requirement, and critical care admission duration. RESULTS: The fast-track extubation group had a shorter postoperative vasopressor requirement (0 vs 2 days; P < .01) and a reduced need for renal replacement therapy (3% vs 21.2%; P = .05). Median critical care admission duration (3 vs 4 days; P = .03) and hospital admission duration (14 vs 19 days; P = .04) were shorter in the fast-track extubation group. CONCLUSIONS: This is the first study to reveal a significant association between fast-track extubation and reduced postoperative vasopressor requirement. Additionally, this was associated with a trend toward reduced renal replacement requirement after liver transplant. It suggests that early extubation may not just be a resource benefit to an institution but may convey a clinical benefit to patients through a reduction in organ failure and requirement for organ support.

Perioperative management of adult cadaveric and live donor renal transplantation in the UK: a survey of national practice.

BACKGROUND: There is a limited evidence base and no national consensus regarding the perioperative management of patients undergoing renal transplantation. We developed an electronic survey to capture an overview of renal transplant perioperative practice across UK renal transplant centres and determine the need for future guidelines on patient management. METHODS: A 29-question survey was developed to encompass the entire renal transplant perioperative pathway and input was sought from clinicians with expertise in renal transplant surgery, anaesthesia, nephrology and intensive care. The survey was sent to lead renal anaesthetists at each of the 23 transplant centres across the UK. RESULTS: A 96% response rate was achieved with 22 out of 23 centres returning complete responses. There was limited evidence of guideline-based approaches to preoperative workup. Questions regarding intraoperative fluid management, blood pressure targets, vasopressor administration and central venous pressure (CVP) monitoring identified a broad range of practice. Of note, the routine use of goal-directed fluid therapy based on cardiac output estimation was reported in six (27.3%) centres, while nine centres (40.9%) continue to target a specific CVP intraoperatively. In all, 12 (54.5%) centres perform transversus abdominis plane blocks with fentanyl-based patient-controlled analgesia as the most common mode of postoperative analgesia. A single centre reported a renal transplant-specific Enhanced Recovery after Surgery programme for cadaveric organ recipients. CONCLUSIONS: This questionnaire highlighted a high degree of heterogeneity in current UK practice as regards the perioperative management of renal transplant recipients. Development of evidence-based national consensus guidelines to standardize the perioperative care of these patients is recommended in order to improve patient outcomes and focus areas of future research.

Pro-coagulant haemostatic factors for the prevention and treatment of bleeding in people without haemophilia.

BACKGROUND: Some hospital patients may be at risk of or may present with major bleeding. Abnormalities of clotting (coagulation) are often recorded in these people, and the traditional management has been with transfusions of blood components, either to prevent bleeding (prophylactic) or to treat bleeding (therapeutic). There is growing interest in the use of targeted therapies with specific pro-coagulant haemostatic (causing bleeding to stop and to keep blood within a damaged blood vessel) factor concentrates in place of plasma. OBJECTIVES: To assess the effects and safety of pro-coagulant haemostatic factors and factor concentrates in the prevention and treatment of bleeding in people without haemophilia. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (2018, issue 3), MEDLINE (from 1948), Embase (from 1974), CINAHL (from 1938), PubMed (publications in process to 18 April 2018), PROSPERO, Transfusion Evidence Library (from 1950), LILACS (from 1980), IndMED (from 1985), KoreaMed (from 1934), Web of Science Conference Proceedings Citation Index (from 1990) and ongoing trial databases to 18 April 2018. SELECTION CRITERIA: We included RCTs that compared intravenous administration of a pro-coagulant haemostatic factor concentrate, either with placebo, current best or standard treatment, or another pro-coagulant haemostatic factor concentrate for prevention or treatment of bleeding. There was no restriction on the types of participants. We excluded studies of desmopressin, tranexamic acid and aminocaproic acid and use of pro-coagulant haemostatic factors for vitamin K over-anticoagulation. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodological procedures. MAIN RESULTS: We identified 31 RCTs with 2392 participants and 22 ongoing trials. There were 13 therapeutic RCTs that randomised 1057 participants (range from 20 to 249 participants) and 18 prophylactic trials that randomised 1335 participants (range 20 to 479 participants). The pro-coagulant haemostatic factor concentrate was fibrinogen in 23 trials, Factor XIII in seven trials and pro-thrombin complex concentrates (PCC) in one trial.Seventeen trials had industrial funding or support, eight studies either did not declare their funding or were unclear about their source of funding and six studies declared non-industrial funding sources.Certainty in the evidence and included study biasOur certainty in the evidence, using GRADE criteria, ranged from very low to high across all outcomes. We assessed most outcomes as being of low certainty. Risks of bias were a concern in many of the RCTs; randomisation methodology was unclear in 15 RCTs, with allocation concealment unclear in 14 RCTs and at high risk of bias in five RCTs. The blinding status of outcome assessors was unclear in 13 RCTs and at high risk of bias in five RCTs, although most outcomes in these trials were objective and not prone to observer bias. Study personnel were often unblinded or insufficient information was available to assess their level of blinding (five RCTs were at unclear risk and seven at high risk of bias).Primary outcomesAll-cause mortality was reported by 21 RCTs, arterial thromboembolic events by 22 RCTs, and venous thromboembolic events by 21 RCTs.Fibrinogen concentrate: prophylactic trials with inactive comparator (nine RCTs)The trials had heterogeneous clinical settings and outcome time points, so we did not pool the data. Compared to placebo, there was no evidence that prophylactic fibrinogen concentrate reduced all-cause mortality (4 RCTs; 248 participants). Compared to inactive comparators there was low- to moderate-quality evidence that prophylactic fibrinogen concentrate did not increase the risk of arterial or venous thromboembolic complications (7 RCTs; 398 participants).Fibrinogen concentrate: prophylactic trials with active comparator (two RCTs)There was no mortality or incidence of thromboembolic events in these two RCTs (with 57 participants).Fibrinogen concentrate: therapeutic trials with inactive comparator (eight RCTs)The trials had heterogeneous surgical settings and outcome time points, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence (quality ranging from low to high) that fibrinogen concentrate reduced all-cause mortality in actively bleeding participants (7 RCTs; 724 participants). Compared to inactive comparators there was no evidence that the use of fibrinogen concentrate in active bleeding increased arterial (7 RCTs; 607 participants) or venous (6 RCTs; 562 participants) thromboembolic events.Fibrinogen concentrate: therapeutic trials with active comparator (four RCTs)We did not pool the outcome data, as they were not measured at comparable time points. Compared to other active pro-coagulant agents, there was no evidence (very low to moderate quality) that fibrinogen concentrate reduced all-cause mortality in actively bleeding participants (4 RCTs; 220 participants). There was no evidence that fibrinogen concentrate increased the risk of arterial (3 RCTs; 126 participants) or venous (4 RCTs; 220 participants) thromboembolic events.FactorXIII: Prophylactic trials with inactive comparator (six trials)The trials were heterogeneous in their surgical settings and time points for outcome analysis, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence that prophylactic Factor XIII reduced all-cause mortality (5 RCTs; 414 participants). There was no evidence (very low to low quality) of a difference in the arterial or venous event rate between Factor XIII and inactive comparators (4 trials; 354 participants).FactorXIII: therapeutic trials with inactive comparator (one trial)There was no mortality or incidence of thromboembolic events in this trial.Prothrombin complex concentrate (PCC): prophylactic trials with inactive comparator (one trial)There was no evidence (moderate quality) that PCC reduced all-cause mortality (1 trial; 78 participants). No thromboembolic complications were reported in this trial. AUTHORS' CONCLUSIONS: The paucity of good-quality comparable evidence precludes the drawing of conclusions for clinical practice. Further research is required to determine the risk-to-benefit ratio of these interventions. The sample sizes of future RCTs would need to be greatly increased to detect a reduction in mortality or thromboembolic events between treatment arms. To improve consistency in outcome reporting, the development of core outcome sets is essential and may help address a number of the limitations identified in this review.

Does the implementation of a novel intensive care discharge risk score and nurse-led inpatient review tool improve outcome? A prospective cohort study in two intensive care units in the UK.

OBJECTIVE: To develop a clinical prediction model for poor outcome after intensive care unit (ICU) discharge in a large observational data set and couple this to an acute post-ICU ward-based review tool (PIRT) to identify high-risk patients at the time of ICU discharge and improve their acute ward-based review and outcome. DESIGN: Retrospective patient cohort of index ICU admissions between June 2006 and October 2011 receiving routine inpatient review. Prospective cohort between March 2012 and March 2013 underwent risk scoring (PIRT) which subsequently guided inpatient ward-based review. SETTING: Two UK adult ICUs. PARTICIPANTS: 4212 eligible discharges from ICU in the retrospective development cohort and 1028 patients included in the prospective intervention cohort. INTERVENTIONS: Multivariate analysis was performed to determine factors associated with poor outcome in the retrospective cohort and used to generate a discharge risk score. A discharge and daily ward-based review tool incorporating an adjusted risk score was introduced. The prospective cohort underwent risk scoring at ICU discharge and inpatient review using the PIRT. OUTCOMES: The primary outcome was the composite of death or readmission to ICU within 14 days of ICU discharge following the index ICU admission. RESULTS: PIRT review was achieved for 67.3% of all eligible discharges and improved the targeting of acute post-ICU review to high-risk patients. The presence of ward-based PIRT review in the prospective cohort did not correlate with a reduction in poor outcome overall (P=0.876) or overall readmission but did reduce early readmission (within the first 48 hours) from 4.5% to 3.6% (P=0.039), while increasing the rate of late readmission (48 hours to 14 days) from 2.7% to 5.8% (P=0.046). CONCLUSION: PIRT facilitates the appropriate targeting of nurse-led inpatient review acutely after ICU discharge but does not reduce hospital mortality or overall readmission rates to ICU.

Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord.

Spinal cord injury often leads to permanent incapacity because long axons cannot regenerate in the CNS. Eph receptors inhibit axon extension through an effect on the actin cytoskeleton. We have previously reported that after injury EphA4 appears at high levels in stumps of corticospinal axons, while a cognate ligand, ephrinB2, is upregulated at the lesion site so as to confine the injured axons. In this study we have infused lesioned spinal cords with a peptide antagonist of EphA4. In treated animals the retrograde degeneration that normally follows corticospinal tract injury is absent. Rather, corticospinal tract axons sprout up to and into the lesion centre. In a behavioural test of corticospinal tract function, peptide treatment substantially improved recovery relative to controls. These results suggest that blocking EphA4 is likely to contribute to a future successful clinical treatment for spinal cord injury.

Molecular and functional characterization of inositol trisphosphate receptors during early zebrafish development.

Fluctuations in cytosolic Ca(2+) are crucial for a variety of cellular processes including many aspects of development. Mobilization of intracellular Ca(2+) stores via the production of inositol trisphosphate (IP(3)) and the consequent activation of IP(3)-sensitive Ca(2+) channels is a ubiquitous means by which diverse stimuli mediate their cellular effects. Although IP(3) receptors have been well studied at fertilization, information regarding their possible involvement during subsequent development is scant. In the present study we examined the role of IP(3) receptors in early development of the zebrafish. We report the first molecular analysis of zebrafish IP(3) receptors which indicates that, like mammals, the zebrafish genome contains three distinct IP(3) receptor genes. mRNA for all isoforms was detectable at differing levels by the 64 cell stage, and IP(3)-induced Ca(2+) transients could be readily generated (by flash photolysis) in a controlled fashion throughout the cleavage period in vivo. Furthermore, we show that early blastula formation was disrupted by pharmacological blockade of IP(3) receptors or phospholipase C, by molecular inhibition of the former by injection of IRBIT (IP(3) receptor-binding protein released with IP(3)) and by depletion of thapsigargin-sensitive Ca(2+) stores after completion of the second cell cycle. Inhibition of Ca(2+) entry or ryanodine receptors, however, had little effect. Our work defines the importance of IP(3) receptors during early development of a genetically and optically tractable model vertebrate organism.

Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion.

Abstract We have examined the expression of Eph receptors and their ephrin ligands in adult rat spinal cord before and after lesion. Neurons in adult motor cortex express EphA4 mRNA, but the protein is undetectable in uninjured corticospinal tract. In contrast, after dorsal column hemisection EphA4 protein accumulates in proximal axon stumps. One of the ligands for EphA4, ephrinB2, is normally present in the grey matter flanking the corticospinal tract but after injury is markedly up-regulated in astrocytes in the glial scar. The result is that, after a lesion, corticospinal tract axons bear high levels of EphA4 and are surrounded to front and sides by a continuous basket of cognate inhibitory ephrin ligand. We suggest that a combination of EphA4 accumulation in the injured axons and up-regulation of ephrinB2 in the surrounding astrocytes leads to retraction of corticospinal axons and inhibition of their regeneration in the weeks after a spinal lesion.

Alkaline phosphatase fusion proteins as affinity probes for protein localization studies.

The receptor affinity probe or receptor alkaline phosphatase (RAP) staining method uses soluble protein ectodomains fused to secreted placental alkaline phosphatase to locate ectodomain binding sites within cells or tissues. We have used this approach to identify expressing cells in tissue culture, in tissue sections, or in whole-mount embryos. The RAP method is especially useful in situations where a reliable monoclonal antibody is not available or if an orphan receptor is the focus of the study. The technique permits localization of both receptors and ligands and is readily quantifiable for cell-surface binding assays. Soluble ectodomain placental alkaline phosphatase fusion proteins are therefore highly sensitive reagents that permit the direct localization of available binding sites through simple chromogenic assays without purification, radioactive labeling, or secondary reagents.