Neutrophil gelatinase-associated lipocalin and liver-type fatty acid-binding protein as biomarkers for acute kidney injury after organ transplantation.

PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) are promising early biomarkers for acute kidney injury (AKI). In organ transplant recipients, AKI predictability based on NGAL and L-FABP remains to be elucidated. Furthermore, the association between serial NGAL and L-FABP measurements and AKI outcome is unknown. Therefore, we conducted a study to evaluate the ability of NGAL and L-FABP to predict AKI after organ transplantation and investigate the association between NGAL, L-FABP and AKI outcome. METHODS: Twenty-five organ transplant recipients admitted to the intensive care unit (ICU) immediately after transplant surgery were studied prospectively. Plasma NGAL (P-NGAL), urinary NGAL (U-NGAL) and L-FABP were measured from ICU admission to ICU discharge. U-NGAL and L-FABP were corrected for dilution/concentration by calculating U-NGAL/urine creatinine ratios (U-NGAL/Cr) and L-FABP/urine creatinine ratios (L-FABP/Cr). AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. RESULTS: AKI occurred in 11 patients. P-NGAL, U-NGAL/Cr and L-FABP/Cr upon ICU admission were unrelated to AKI development (p = 0.24, 0.22, and 0.53, respectively). There were no differences in P-NGAL, U-NGAL/Cr, and L-FABP/Cr levels from day 1 to day 6 between patients who did not recover from AKI and patients who recovered from AKI (p = 0.82, 0.26, and 0.61, respectively). CONCLUSION: Our findings suggest that NGAL and L-FABP upon ICU admission are not predictive of AKI and serial NGAL and L-FABP measurements may be ineffective for monitoring the status and treatment of post-transplantation AKI.

Perioperative fluid balance affects staging of acute kidney injury in postsurgical patients: a retrospective case-control study.

BACKGROUND: Although Acute Kidney Injury Network (AKIN) staging is widely used, it has been suggested that classification using serum creatinine levels, which fluctuate because of fluid balance, is not always appropriate for acute kidney injury (AKI) detection. We hypothesized that some patients are misdiagnosed as having no AKI due to dilution resulting from intraoperative infusion, and have worse outcomes than typical patients with no AKI. METHODS: We retrospectively selected patients who did not fulfill the AKI criteria from those who underwent cardiac surgery and remained in an intensive care unit (ICU) for ≥7 days. The patients were divided into two groups: those with AKI (AKI group) and those without AKI (no-AKI group), classified using serum creatinine levels adjusted for fluid balance during the perioperative period. We compared the characteristics and outcomes of the two groups. RESULTS: After adjustment for serum creatinine, 7 of 26 patients were categorized as having AKI. The AKI group had significantly fewer ventilator-free days during a 28-day period and significantly longer ICU stays than the no-AKI group (5.86 ± 10.0 days vs. 15.6 ± 9.71 days, respectively, P = 0.050; 36.4 ± 20.6 days vs. 14.9 ± 10.7 days, respectively, P = 0.033). CONCLUSION: Adjustment of creatinine level for perioperative fluid balance could improve the accuracy of AKI diagnosis after cardiac surgery.

Early prediction of acute kidney injury biomarkers after endovascular stent graft repair of aortic aneurysm: a prospective observational study.

BACKGROUND: Acute kidney injury (AKI) is a common and serious condition usually detected some time after onset by changes in serum creatinine (sCr). Although stent grafting to repair aortic aneurysms is associated with AKI caused by surgical procedures or the use of contrast agents, early biomarkers for AKI have not been adequately examined in stent graft recipients. We studied biomarkers including urinary neutrophil gelatinase-associated lipocalin (NGAL), blood NGAL, N-acetyl-ß-d-glucosaminidase (NAG), microalbumin (Alb), and liver fatty acid-binding protein (L-FABP) as prospective early biomarkers for AKI in patients who had received stent graft repairs of aortic aneurysms. METHODS: In addition to pre-surgical sampling, at 2 to 6 h and at 1, 3 to 4, and 5 days or later (until stable) after surgery, urine and serum biomarkers were sampled from 47 patients who underwent stent graft repair of aortic aneurysms. RESULTS: Using Acute Kidney Injury Network criteria, 6 (14%) of 42 retained patients developed AKI. NGAL corrected with urine Cr (NGAL/Cr) values demonstrated the best predictive value for AKI (97% specificity, 83% sensitivity at a 65.1 µg/gCr cutoff). The area under the receiver-operator characteristic curve of NGAL/Cr value 2 h after surgery was 0.9. Although NGAL/Cr, L-FABP corrected with urine Cr (L-FABP/Cr), L-FABP, NAG, and Alb corrected by urine Cr (Alb/Cr) all reached peak values before AKI detection by sCr in AKI patients, all biomarkers reached the cutoff value before AKI detection after adaption of cutoff value. CONCLUSIONS: After stent graft repair of aortic aneurysm, NGAL/Cr is a potentially useful early biomarker for AKI.

[Sugammadex reversal after extubation under muscle relaxation to prevent cough reflex in a patient with intractable spontaneous pneumothorax].

A 40-year-old man (168 cm tall and weighing 71 kg) with intractable pneumothorax was operated for resection of a bulla in the left lung. After insertion of epidural catheter via T 5-6 interspace, general anesthesia was induced and maintained with propofol, remifentanil and rocuronium. The duration of surgery was 1h 48 min and rocuronium given during surgery was 110 mg. After completion of surgery, the double-lumen tube was replaced with laryngeal mask airway to prevent cough reflex. However, infusion of sugammadex 200 mg induced mild cough reflex, resulting in air leakage from thoracic drainage. Because air leakage still continued after extubation, reoperation must be done and re-intubation was required. Since rocuronium 50 mg did not provide satisfactory muscle relaxation measured by train of four, additional dose of rocuronium 40 mg was administered and re-intubation was successfully performed without cough reflex. Reoperation lasted for 43 minutes and rocuronium infused was 100 mg. Nasal airway was inserted to prevent airway obstruction by the tongue and extubation was performed under muscle relaxation with infusion of rocuronium 10 mg. And then, immediate administration of sugammadex 400 mg could elicit spontaneous respiration without cough reflex.

Influence of humidification on comfort during noninvasive ventilation with a helmet.

OBJECTIVE: To evaluate optimal humidifier water temperature when using a helmet for noninvasive ventilation. METHODS: Twenty-eight healthy individuals underwent 8 cm H2O CPAP ventilation with FIO2 of 0.21 and 0.5. Each was sequentially tested in the following order: using the helmet without humidification at ambient temperature; with humidification with unheated chamber water; and with humidification with the chamber water at 31°C, 34°C, and 37°C. At each setting, after a 20 min stabilization period, measurements were taken. Comfort level at each setting was evaluated using a visual analog scale rated zero (least comfortable) to 10 (most comfortable). RESULTS: Temperature and relative and absolute humidity inside the helmet increased; however, the comfort scores significantly decreased as the humidification chamber water temperature increased. Regardless of the FIO2, statistically significantly highest comfort scores were obtained when humidification water, with and without active humidification, was at ambient temperature. Unacceptable absolute humidity was obtained only without humidification at room temperature when FIO2 was 0.5. CONCLUSIONS: With the clinical use of a helmet, for patient comfort and mucosal humidification during CPAP, the most desirable conditions are likely to be obtained by humidifying without heating, that is by leaving the water in the humidifier chamber at room temperature.

Antiallodynic and antihyperalgesic effect of milnacipran in mice with spinal nerve ligation.

BACKGROUND: The antidepressant, milnacipran, has been reported to have antinociceptive, antiallodynic, and antihyperalgesic effects. In this study, we examined the mechanisms of the antiallodynic and antihyperalgesic effects of milnacipran in a model of neuropathic pain induced by spinal nerve ligation in mice. METHODS: The fifth left lumbar nerve of male C57BL6 mice was tightly ligated. Withdrawal threshold to tactile stimulation and withdrawal latency to heat stimulation in the injured or contralateral paw was tested by using von Frey filaments and radiant heat, respectively. RESULTS: Milnacipran was administered either orally (7.5-120 mg/kg), intrathecally, intracerebroventricularly, or locally (210 ng-21 microg). Both systemic, intrathecal and intracerebroventricular milnacipran increased withdrawal threshold and withdrawal latency in nerve-ligated mice whereas local injection had no effect. Depletion of spinal serotonergic or noradrenergic neurons was achieved by use of the specific neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine, applied intrathecally 3 days before evaluation of the analgesic effect of milnacipran. Spinal serotonergic and noradrenergic denervation attenuated the effect of milnacipran in sham-operated mice. In nerve-ligated mice, however, the effect of milnacipran was lost after noradrenergic denervation but not after serotonergic denervation. CONCLUSIONS: We concluded that the antiallodynic and antihyperalgesic effects of milnacipran on neuropathic pain induced by spinal nerve ligation are principally mediated through action at supraspinal and spinal sites via activation of the spinal noradrenergic system.

[The relationship of individual sensitivities to fentanyl and those to propofol].

BACKGROUND: Individual variation in the sensitivity to anesthetics induces the delayed awakening and the severe postoperative pain at an inappropriate dose. We designed the study to see the correlation of the individual sensitivity to fentanyl and that to propofol which have different mechanism. METHODS: General anesthesia was induced using target controlled infusion system of fentanyl and propofol. Fentanyl effect-site concentration gradually increased towards a target plasma concentration of 3 ng x ml(-1) until the appearance of the subjective symptom such as dizziness, a sensation of warmth and other reactions. After this, propofol effect-site concentration gradually increased towards a target plasma concentration of 4 microg x ml(-1) until loss of consciousness (LOC). The effect-site concentrations of fentanyl at the symptom and propofol at loss of consciousness were measured. RESULTS: The correlation between the estimated effect-site concentration of fentanyl and propofol is not significant in the whole patient. However, a positive correlation between fentanyl and propofol was found in patients from 50s to 70s years of ages (r = 0.59). CONCLUSIONS: The correlation of the individual sensitivity to fentanyl and propofol was found in older age groups.

Local anesthetics have different mechanisms and sites of action at recombinant 5-HT3 receptors.

BACKGROUND AND OBJECTIVES: In addition to their blockade of voltage-dependent sodium channels, the action of local anesthetics at 5-hydroxytryptamine-3 (5-HT3) receptors may be clinically relevant. Because local anesthetics have different clinical properties, we have tested the hypothesis that differences in interactions at the 5-HT3 receptor may be clinically relevant by investigating the effects of 4 local anesthetics on recombinant wild-type and 4 mutant 5-HT3A receptors. METHODS: The cRNAs from human wild-type and 4 mutant 5-HT3A subunit clones were synthesized in vitro and expressed in Xenopus oocytes. Four mutant receptors were obtained by site-directed mutagenesis in the N-terminal extracellular region, which contains the agonist binding domain. Tryptophan (W) at positions 62 and 155 were replaced by tyrosine (Y) and glutamate (E) at position 101 by aspartate (D) or asparagine (N). The 2-electrode voltage clamp technique was used to measure peak currents induced by 5-HT in these receptors in the presence and absence of local anesthetics. RESULTS: All local anesthetics inhibited 5-HT-induced currents in a dose-dependent manner in the wild-type receptor. Inhibition by procaine and tetracaine were competitive whereas those of bupivacaine and lidocaine were both noncompetitive and competitive. The 4 mutants (W62Y, W155Y, E101D, E101N) could all form functional receptors. All mutant receptors exhibited a major increase (> 10-fold) in the half-maximum inhibitory concentration for procaine. The half-maximum inhibitory concentrations of tetracaine, bupivacaine, and lidocaine in mutant receptors were increased 2- to 3-fold except that of tetracaine in W62Y receptor (6-fold). CONCLUSIONS: The ester type local anesthetics, procaine and tetracaine, may act at a different site on the 5-HT(3A) receptor and with a different mechanism than the amide-type local anesthetics. Clinical differences between local anesthetics may be at least partially due to differences in interactions at the 5-HT3A receptor.

[Adsorption of local anesthetic into disposable infusion balloon].

BACKGROUND: The aim of this study was to investigate the adsorption of local anesthetics lidocaine and ropivacaine, into disposable infusion balloons made from various kinds of plastics. METHODS: The concentration of local anesthetic that flows out of a balloon was measured. RESULTS: The concentration of both lidocaine and ropivacaine in clinical formula decreased only 4.5 percent regardless of infusion balloons. However, the concentration of lidocaine pH 7.4 decreased by 10 percent in the Syrinjector made from polypropylene and polyvinyl chloride, and that of 18-20 percent in other infusion balloons (Surefuser, Baxtor Infuser, DIB Catheter made from isoprene rubber and polyvinyl chloride, isoprene rubber and polyvinyl chloride, silicon and polyvinyl chloride, respectively). CONCLUSIONS: The adsorption of local anesthetic into infusion balloons has little effect in clinical situation. Whereas, in case of lidocaine pH 7.4, the adsorption depends on the specific type of plastics.

In vitro antagonism of recombinant ligand-gated ion-channel receptors by stereospecific enantiomers of bupivacaine.

BACKGROUND AND OBJECTIVES: Bupivacaine is a racemic mixture of S(-)- and R(+)-enantiomers. Both isomers have similar potency as local anesthetics, but the S(-)-enantiomer produces less central nervous system and cardiovascular toxicity. Local anesthetic-induced convulsion is likely to be associated with not only sodium channel but also ligand-gated ion channel. The present study investigates the direct effects of the stereoenantiomers of bupivacaine on 4 recombinant ligand-gated ion-channel receptors. METHODS: The antagonist activities of the S(-)- and R(+)-enantiomers of bupivacaine were tested at the nicotinic acetylcholine, N-methyl-d-aspartate (NMDA), gamma-aminobutyric acid(A) (GABA(A)), and 5-hydroxytryptamine(3A) (5-HT(3A)) receptors expressed in Xenopus oocytes using a 2-voltage clamp technique. RESULTS: Racemic bupivacaine and its 2 enantiomers all antagonized the 4 receptors in a concentration-dependent manner. Potencies at nicotinic acetylcholine, NMDA, and 5-HT(3A) receptors were similar. At GABA(A) receptors, the potency of R(+)-bupivacaine was less than racemic bupivacaine or levobupivacaine. CONCLUSIONS: Comparison of the antagonist potencies with local concentrations obtained in clinical use suggests that bupivacaine and its enantiomers are likely to produce extensive inhibition at the nicotinic acetylcholine, NMDA, and 5-HT(3A) receptors but a much weaker and probably not clinically relevant effect at the GABA(A) receptor. It is possible that direct effects at these receptors may contribute, at least in part, to the spinal and epidural anesthesia induced by these compounds. It is unlikely, however, that the difference of the toxicity in bupivacaine enantiomers is because of the stereoselectivities of bupivacaine at ligand-gated ion-channel receptors studied.

In vitro inhibition of recombinant ligand-gated ion channels by high concentrations of milnacipran.

RATIONALE: Tricyclic antidepressants are known to inhibit various ligand-gated ion-channel (LGIC) receptors, and some of their clinical features may be associated with this activity. The effects of milnacipran, a selective inhibitor of the reuptake of serotonin and noradrenaline, on LGIC receptors have not yet been investigated on such ion-channel receptors. OBJECTIVES: To determine the in vitro effect of milnacipran on four recombinant LGIC receptors, nicotinic acetylcholine, N-methyl-D-aspartate, gamma-amino butyric acid (GABA) and 5-hydroxytryptamine3A receptors. METHODS: Receptors were expressed in Xenopus oocytes and LGIC activity measured using a two-voltage clamp technique. RESULTS: There was no interaction at the GABA receptor. The results at the other LGIC receptors showed that they could be inhibited by high concentrations of milnacipran. CONCLUSIONS: At high concentrations, milnacipran can inhibit certain LGICs. It is, however, unlikely that these interactions have any clinical consequence under normal therapeutic conditions, since the concentrations required are considerably higher than those achieved in plasma of treated patients.

A small preoperative test dose of intravenous fentanyl can predict subsequent analgesic efficacy and incidence of side effects in patients due to receive epidural fentanyl.

UNLABELLED: Because individual variation is a likely factor affecting both the incidence and severity of side effects and the analgesic efficacy of epidural opioids, assessment of individual variation could be useful in deciding optimal dosage. By evaluating the response to a small test dose of IV fentanyl, we designed this study to predict the degree of pain relief and the incidence of side effects in patients who would be receiving postoperative epidural fentanyl. Before the induction of anesthesia, 50 micro g of fentanyl was administered IV, and 2 min after fentanyl, the patient response was evaluated. Twenty-three patients, who reported nausea, sleepiness, dizziness, sensation of warmth, and other symptoms, were categorized as responders (Group R); the remaining 20 patients were categorized as nonresponders (Group NR). At the completion of surgery, infusion of epidural fentanyl was administered (0.3 mg/d in 0.25% bupivacaine) for 96 h. At postoperative Hours 6 and 24, Group R had significantly lower visual analog scale scores for postoperative pain intensity and required fewer analgesics than Group NR. The incidence of side effects, however, was 74% for Group R and 10% for Group NR (P < 0.05), and side effects were more serious in Group R. This study demonstrates that preoperative administration of a small dose of fentanyl during the induction of anesthesia enables prediction of the analgesic efficacy of postoperative epidural fentanyl and the incidence and severity of side effects. IMPLICATIONS: Preoperative administration of a small dose of fentanyl during the induction of anesthesia enables prediction of the analgesic efficacy of postoperative epidural fentanyl and the incidence and severity of side effects.

Nitrous oxide and xenon inhibit the human (alpha 7)5 nicotinic acetylcholine receptor expressed in Xenopus oocyte.

The neuronal nicotinic acetylcholine (nACh) receptor is one of the ligand-gated ion channels that regulate the synaptic release of neurotransmitters in the central nervous system. Recently, neuronal nACh receptors have received attention as a potential target for general anesthetics because many general anesthetics inhibit their functions at clinical concentrations. Several general anesthetics are known to inhibit the homomeric (alpha(7))(5) nACh receptor, a subtype of neuronal nACh receptors, but the effects of two gaseous anesthetics, nitrous oxide (N(2)O) and xenon (Xe), remain unknown. Using the two-electrode voltage-clamping technique, we investigated the effects of N(2)O and Xe at the human (alpha(7))(5) nACh receptor expressed in Xenopus oocytes. At clinically relevant concentrations, N(2)O and Xe reversibly inhibited the ACh-induced currents of the (alpha(7))(5) nACh receptor in a concentration-dependent manner. The inhibitory actions of both anesthetics at the (alpha(7))(5) nACh receptor were noncompetitive and voltage-independent. Our results suggest that inhibition of the (alpha(7))(5) nACh receptor by N(2)O and Xe may play a role in their anesthetic effects.