Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness

OBJECTIVE Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN Critically ill adults (n=40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n=10), GHRH and GHRP-2 (n=10), GHRP-2 and GHRH+GHRP-2 (n=10), GHRH+GHRP-2 and GHRH+GHRP-2+TRH (n=10). The GHRH and GHRP-2 doses were 1μg/kg and the TRH dose was 200μg. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection. MEASUREMENTS Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA. RESULTS Critically ill patients presented a striking GH response to GHRP-2 (mean±SEM peak GH 51±9 μg/l in older patients and 102±2μg/l in younger patients; P=0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P=0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P=0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P=0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response < ninefold (P=0.005), elicited a 60% rise in serum T3 (P=0.01) and an 18% increase in T4 (P=0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P=0.007). GHRP-2 increased basal serum cortisol levels (531±29nmol/l) by 35% (P=0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P=0.05). CONCLUSIONS The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.     

Elective single day 3 embryo transfer halves the twinning rate without decrease in the ongoing pregnancy rate of an IVF/ICSI programme

BACKGROUND: Data on the effect of elective single embryo transfer (eSET) on the total and multiple pregnancy rates of an IVF/ICSI programme are reported. METHODS AND RESULTS: A retrospective cohort analysis of eSET was carried out over a 4 year period. A total of 1559 cycles resulted in 1464 transfers; 299 transfers of one top quality embryo (20.4%) and 86 of one non-top quality embryo (5.9%) yielded 149 conceptions (49.8%) with 105 ongoing pregnancies (35.1%) and 26 conceptions (30.2%) with 19 ongoing implantations (22.1%) respectively; 1079 transfers of two (n = 853; 58.3%) or more than two (n = 226; 15.4%) embryos yielded 366 ongoing pregnancies (33.9%). The ongoing pregnancy rates for the years between 1998 and 2001 were 35.9, 27.9, 31.9 and 31.0% per oocyte retrieval and 38.5, 29.4, 34.1 and 33.2% per transfer. There were no differences in pregnancy rates between any of the years. The average ongoing pregnancy rate (>12 weeks) over the 4 years was 31.5% per started cycle and 33.5% per transfer; the average number of embryos transferred decreased from 2.26 (1998) to 1.79 (2001); the multiple pregnancy and twinning rates dropped from 33.6 and 29.5% (1998) to 18.6 and 16.3% (2001) respectively. CONCLUSIONS: Judicious application of eSET can halve the twinning rate while maintaining the overall pregnancy rate.     

Active PAI-1 as marker for venous thromboembolism: Case–control study using a comprehensive panel of PAI-1 and TAFI assays

Background

Both activated Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and active Plasminogen Activator Inhibitor-1 (PAI-1) attenuate fibrinolysis and may therefore contribute to the pathophysiology of Venous ThromboEmbolism (VTE). Whether increased TAFI and/or PAI-1 concentrations are associated with VTE is unclear.

Objective

To study an association of impaired fibrinolysis and VTE using a comprehensive panel of in-house developed assays measuring intact TAFI, activation peptide of TAFI (AP-TAFI), PAI-1 antigen, endogenous PAI-1:t-PA complex (PAI-1:t-PA) and active PAI-1 levels in 102 VTE patients and in 113 healthy controls (HC).

Results

Active PAI-1 was significantly higher in VTE patients compared to HC (20.9 [9.6-37.8] ng/ml vs. 6.2 [3.5-9.7] ng/ml, respectively). Active PAI-1 was the best discriminator with an area under the ROC curve and 95% confidence interval (AUROC [95%CI]) of 0.84 [0.79-0.90] compared to 0.75 [0.68-0.72] for PAI-1:t-PA, 0.65 [0.58-0.73] for PAI-1 antigen, 0.62 [0.54-0.69] for AP-TAFI and 0.51 [0.44-0.59] for intact TAFI. Using ROC analysis, we defined an optimal cut-off of 12.8 ng/ml for active PAI-1, with corresponding sensitivity of 71 [61–79] % and specificity of 89 [82–94] %. A lack of association with the time between VTE event and sample collection or with the intake of anticoagulant treatment suggests that active PAI-1 levels are sustainable high in VTE patients.

Conclusions

This case–control study emphasizes the clinical importance of measuring active PAI-1 instead of PAI-1 antigen and identifies active PAI-1 as a potential marker of VTE. Prognostic studies will need to address the clinical significance of active PAI-1 as biomarker.     

Impact of Early Parenteral Nutrition on Metabolism and Kidney Injury

A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.The development of AKI is a frequent and devastating condition in patients admitted to the intensive care unit (ICU). Short-term mortality is high and increases with worsening AKI stages.¹ In AKI survivors, renal recovery is often incomplete, progression to ESRD may be accelerated, and longer-term mortality rates are increased compared with non-AKI patients.^2,3 Patient management consists of maximal prevention of additional renal damage by hemodynamic stabilization and prevention of (iatrogenic) nephrotoxicity. A curative strategy for established AKI is currently unavailable.⁴Observational studies, finding associations between a poor nutritional state and increased morbidity and mortality of AKI patients⁵ and between accumulation of a caloric deficit and poor renal and survival outcome of ICU patients,^6,7 have led to the hypothesis that feeding could ameliorate kidney injury and improve survival of ICU patients. However, nutrition, especially parenteral nutrition (PN), also has potential complications.^8–11 Because of the lack of adequately designed studies, nutritional guidelines are largely based on expert opinion.^12–14 These opinions invariably recommend the early initiation of enteral feeding but substantially differ in their recommendation on when to start supplemental PN.The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study was the first large, multicenter, randomized controlled trial (RCT) addressing this important question. The study showed that early initiation of PN increased dependency on intensive care compared with withholding supplemental PN for 1 week (hereafter labeled early PN and late PN, respectively).¹⁵ Indeed, early PN prolonged the ICU and hospital length of stay (LOS), increased the incidence of new infections, and prolonged the need for mechanical ventilation. Renal harm was suggested by a clear prolongation of the duration of renal replacement therapy (RRT) in ICU and a trend for more AKI (defined as a doubling or more of ICU admission plasma creatinine). However, the number of patients requiring RRT was unaltered, and recovery to premorbid kidney function was not investigated.It was preplanned to study the detailed impact of early versus late PN on the incidence and recovery of AKI and the time course of blood/urine markers of renal function during ICU stay.¹⁶ A priori, we hypothesized that early PN would attenuate kidney injury. However, the original study findings suggested that AKI incidence and renal recovery could be aggravated by increased macronutrient provision in the acute phase of critical illness.     

A comparison of jaw dimensional and quality assessments of bone characteristics with cone-beam CT, spiral tomography, and multi-slice spiral CT

PURPOSE: For proper preoperative planning of oral implants, the need has increased for tomographic imaging for precise determination of anatomic dimensions. However, concern for radiation exposure, which is substantial with computerized tomography (CT), has also grown. In the present study, the validity of jawbone width assessment and delineation by means of cone-beam CT (CBCT) and spiral tomography on dry mandibles was compared. Secondly, the subjective image quality of CBCT images with those obtained by multi-slice spiral CT (MSCT) of a fixed ex vivo cadaver with its soft tissues was compared. MATERIALS AND METHODS: The study included 25 dry human mandibles for the dimensional study and 1 formalized maxilla for image quality assessment. Measurements of the mandibles by means of a digital sliding caliper acted as the gold standard. Radiographic examination of the premolar and canine regions was performed with both CBCT and spiral tomography. Observational measurements were carried out by postgraduates in oral imaging. Subjective image quality was assessed on the fixed maxilla, including soft tissues, by comparing CBCT and MSCT. Inter- and intraobserver variability were determined. RESULTS: Direct mandibular measurements were on average 0.23 mm (SD 0.49) and 0.34 mm (SD 0.90) larger than the CBCT and spiral tomography measurements, respectively. Subjective image quality of the CBCT was significantly better than for the MSCT with regard to visualization and delineation of the lamina dura and periodontal ligament space. Subjective image quality of the MSCT was significantly better for the MSCT than the CBCT for the gingiva and cortical bone. CONCLUSIONS: These results indicate that on dry mandibles, jawbone width measurements by means of CBCT and spiral tomography are reliable, even if on average they slightly underestimate the bone width. For the subjective image quality, the CBCT offered better visualization of details of the small bony structures. Spiral tomography offered better visualization of the cortical bone and the gingiva.     

External validation of severity scoring systems for acute renal failure using a multinational database

OBJECTIVE: Several different severity scoring systems specific to acute renal failure have been proposed. However, most validation studies of these scoring systems were conducted in a single center or in a small number of centers, often the same ones used for their development. Therefore, it is not known whether such severity scoring systems may be widely applied. DESIGN: Prospective clinical investigation. SETTING: Intensive care units. PATIENTS: One thousand seven hundred and forty-two intensive care unit patients with acute renal failure who were either treated with renal replacement therapy or fulfilled predefined criteria. INTERVENTIONS: Demographic and clinical information and outcomes were measured. MEASUREMENTS AND MAIN RESULTS: Scores for four acute renal failure-specific scoring systems and two general scoring systems (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment) were calculated, and their discrimination and calibration were tested with receiver operating characteristic curves and Hosmer-Lemeshow goodness-of fit-tests. For the receiver operating characteristic curves, blood lactate levels were also used as a reference. All scores had an area under the receiver operating characteristic curve <0.7 (Mehta 0.670, Liano 0.698, Chertow 0.610, Paganini 0.643, Simplified Acute Physiology Score II 0.645, Sequential Organ Failure Assessment 0.675, lactate 0.639). For scores that can calculate predicted mortality, the Hosmer-Lemeshow goodness-of-fit test showed poor calibration. CONCLUSIONS: None of the scoring systems tested had a high level of discrimination or calibration to predict mortality for patients with acute renal failure when tested in a broad cohort of patients from multiple countries. A large, multiple-center database might be needed to improve the discrimination and calibration of acute renal failure scoring system.