Primary spread of caudal blockade in children: the possible limiting role of the lumbar spinal cord enlargement (tumenescence) in combination with the cerebrospinal fluid rebound mechanism.

BACKGROUND: Despite being the most frequently used pediatric nerve block, certain aspects of the initial intraspinal spread of local anesthetics when performing a caudal block need further elucidation. The fact that injected volumes of 0.7-1.3 mL kg-1 initially only reach the thoraco-lumbar junction, with only a few vertebral segments difference despite the huge difference in injected volume, still has no apparent explanation. We hypothesize that the narrowing of the epidural space caused by the lumbar spinal enlargement may provide an anatomical barrier causing this restriction of initial spread, alone or in combination with increased intrathecal pressure caused by the "cerebrospinal fluid rebound mechanism." The aim of this observational study was to find support for or refute this hypothesis. METHODS: Twenty nine MRI scans of the vertebral column, performed in children 0-6 years of age, was identified from the radiographic imaging computer system and analyzed for the vertebral level of the maximum of the lumbar spinal enlargement (Associated anatomical data related to the spinal canal, the dura mater, and the spinal cord were also recorded. RESULTS: The maximum of the lumbar spinal enlargement was found at a median vertebral level of Th 11 (IQR 11-11). CONCLUSION: The maximum of the lumbar spinal enlargement is located at the Th 11 vertebral level. Although not entirely conclusive, the findings of the present study do support the notion that the lumbar spinal enlargement, in combination with the CSF rebound mechanism, may be the factors limiting the initial spread of a caudal block to the thoraco-lumbar junction.

Cerebral blood flow alterations associated with high volume caudal block in infants.

BACKGROUND: High-volume (1.5 ml kg-1) caudal block in infants results in major reductions of cerebral blood flow velocity (CBFV) and cerebral oxygenation, caused by rostral CSF movement which increases intracranial pressure. The primary aim of this study was to determine the relationship between injected volume and CBFV changes. We hypothesised that this volume-blood flow relationship would have a similar albeit inverted shape to the well-known intracranial pressure volume-pressure curve. METHODS: Fifteen subjects, age 0-6 months, mean (range) weight 4.9 (2.1-6.4) kg, were studied. A 1.5 ml kg-1 caudal injection of 0.2% ropivacaine was administered in three phases separated by two pauses. Subjects were randomised into five groups, in whom the pauses were implemented at different pre-set proportions of the total injected volume. Middle cerebral artery Doppler ultrasonography was used for CBFV measurements (Vmax, peak CBF velocity; Vmin, lowest CBF velocity; velocity time index). Mean flow velocity, pulsatility index, and resistivity index were calculated, and haemodynamic parameters were recorded. RESULTS: CBFV parameters decreased in all patients. The most affected parameter, Vmin, was reduced by ∼50% (range 15-68%) compared with baseline. There was a nonlinear relationship between the volume of the first phase injection and the CBFV measurement during the first pause. Across all time points, there was a linear relationship between volume administered and CBFV. Systemic haemodynamic parameters remained stable throughout the study. CONCLUSIONS: Injection pauses appear to attenuate adverse CBFV increases during administration of a high-volume caudal block.

Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep.

INTRODUCTION: Acute kidney injury (AKI) is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 (TLR4) would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed. METHODS: Sheep were surgically instrumented and subjected to a 36-hour intravenous infusion of live Escherichia coli. After 12 hours, they were randomized to treatment with a selective TLR4 inhibitor (TAK-242) or vehicle. RESULTS: The E. coli caused normotensive sepsis characterized by fever, increased cardiac index, hyperlactemia, oliguria, and decreased creatinine clearance. TAK-242 significantly improved creatinine clearance and urine output. The increase in N-acetyl-beta-D-glucosaminidas, a marker of tubular damage, was attenuated. Furthermore, TAK-242 reduced the renal neutrophil accumulation and glomerular endothelial swelling caused by sepsis. These effects were independent of changes in renal artery blood flow and renal microvascular perfusion in both cortex and medulla. TAK-242 had no effect per se on the measured parameters. CONCLUSIONS: These results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis. In addition, the results provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro-circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis. TLR4-mediated inflammation resulting in glomerular endothelial swelling may be an important part of the pathogenesis underlying Gram-negative septic acute kidney injury.

Toll-like receptor 4 inhibitor TAK-242 attenuates acute kidney injury in endotoxemic sheep.

BACKGROUND: This study was conducted to investigate the role of toll-like receptor 4 (TLR4) in mediating acute kidney injury in endotoxemic sheep using the selective TLR4 inhibitor TAK-242. METHODS: A randomized, controlled, experimental study was performed with 20 adult Texel crossbred sheep. Before an Escherichia coli lipopolysaccharide infusion (3 µg · kg(-1) · h(-1) for 24 h), sheep were randomized to receive a bolus dose (2 mg/kg), followed by a continuous infusion (4 mg · kg(-1) · 24 h(-1)) of either TAK-242 (n = 7) or vehicle (n = 7). A third group of lipopolysaccharide-treated sheep (n = 6) received norepinephrine, titrated to maintain baseline arterial blood pressure. RESULTS: Endotoxin infusion established a state of hyperdynamic circulation, with an increased cardiac index, hypotension, and tachycardia. Urine output and creatinine clearance decreased throughout the experiment, together with increasing plasma creatinine, blood urea nitrogen, and arterial lactate concentrations. After 24 h, TLR4 inhibition had significantly (P ≤ 0.001) attenuated the mean ± SEM decrease in arterial pressure (97 ± 3 vs. 71 ± 4 mmHg), urine output (1.16 ± 0.15 vs. 0.13 ± 0.05 ml · kg(-1) · h(-1)), and creatinine clearance (126 ± 13 vs. 20 ± 7 ml/min) compared with vehicle-treated animals. Furthermore, arterial lactate, plasma creatinine, and blood urea nitrogen concentrations were significantly lower in the TAK-242 group versus the vehicle-treated animals. Compared with TLR4 inhibition, norepinephrine caused similar effects on arterial pressure, cardiac index, and heart rate; however, it did not attenuate the decrease in urine output or creatinine clearance. CONCLUSIONS: These results indicate a critical role for TLR4 in impairing renal function during ovine endotoxemia that is independent of changes in central hemodynamics.

Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs.

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury.