Jan van Egmond

Tourniquet pain: a volunteer study

The effect of inflation pressure (300 and 400 mm Hg) and method of exsanguination (gravity and Esmarch bandage) on the time of onset and the severity of tourniquet-induced pain in the lower extremity was investigated in 11 unmedicated adult volunteers. Each volunteer underwent eight experiments in a random order. A visual analog scale was used to assess pain and discomfort. Blood pressure and pulse rate were measured continuously. Experiments were concluded when the pain rose to a prefixed level. All experiments were performed using a standard orthopedic tourniquet (7 cm wide). Ten additional experiments were carried out using a Bier blockade tourniquet (5 cm wide). There were no differences in duration of tourniquet inflation between inflation pressures not between methods of exsanguination. There was a small and transient but nevertheless statistically significant increase in blood pressure caused by inflation and a significantly larger increase just before deflation. The 5-cm tourniquet experiments, otherwise identical to the 7-cm tourniquet experiments, were tolerated significantly longer due to a longer time of onset and less severe pain. The 5-cm tourniquet also needed significantly higher inflation pressures to fully occlude the arterial supply (240–450 mm Hg). In all instances, 260 mm Hg was adequate to fully occlude the arterial supply when a 7-cm tourniquet was used. Only half of the experiments were concluded due to intolerable pain at the site of the tourniquet. Most of the others were concluded due to pain mainly in the calf or pain throughout the leg. We conclude that the clinical syndrome of “tourniquet pain” consists of several components and is not due just to the pain and pressure under the tourniquet.

Low-tidal-volume mechanical ventilation induces a toll-like receptor 4-dependent inflammatory response in healthy mice.

Background:Mechanical ventilation (MV) can induce ventilator-induced lung injury. A role for proinflammatory pathways has been proposed. The current studies analyzed the roles of Toll-like receptor (TLR) 4 and TLR2 involvement in the inflammatory response after MV in the healthy lung. Methods:Wild-type (WT) C57BL6, TLR4 knockout (KO), and TLR2 KO mice were mechanically ventilated for 4 h. Bronchoalveolar lavage fluid was analyzed for presence of endogenous ligands. Lung homogenates were used to investigate changes in TLR4 and TLR2 expression. Cytokines were measured in lung homogenate and plasma, and leukocytes were counted in lung tissue. Results:MV significantly increased endogenous ligands for TLR4 in bronchoalveolar lavage fluid and relative messenger RNA expression of TLR4 and TLR2 in lung tissue. In lung homogenates, MV in WT mice increased levels of keratinocyte-derived chemokine, interleukin (IL)-1α, and IL-1β. In TLR4 KO mice, MV increased IL-1α but not IL-1β, and the increase in keratinocyte-derived chemokine was less pronounced. In plasma, MV in WT mice increased levels of IL-6, keratinocyte-derived chemokine, and tumor necrosis factor α. In TLR4 KO mice, MV did not increase levels of IL-6 or tumor necrosis factor α, and the response of keratinocyte-derived chemokine was less pronounced. MV in TLR2 KO mice did not result in different cytokine levels compared with WT mice. In WT and TLR2 KO mice, but not in TLR4 KO mice, MV increased the number of pulmonary leukocytes. Conclusions:The current study supports a role for TLR4 in the inflammatory reaction after short-term MV in healthy lungs. Increasing the understanding of the innate immune response to MV may lead to future treatment advances in ventilator-induced lung injury, in which TLR4 may serve as a therapeutic target.

Mechanical ventilation in healthy mice induces reversible pulmonary and systemic cytokine elevation with preserved alveolar integrity : An in vivo model using clinical relevant ventilation settings

Background:Mechanical ventilation (MV) may activate the innate immune system, causing the release of cytokines. The resulting proinflammatory state is a risk factor for ventilator-induced lung injury. Cytokine increase results from direct cellular injury but may also result from cyclic stretch alone as demonstrated in vitro: mechanotransduction. To study mechanotransduction in vivo, the authors used an animal MV model with clinically relevant ventilator settings, avoiding alveolar damage. Methods:Healthy C57BL6 mice (n = 82) were ventilated (tidal volume, 8 ml/kg; positive end-expiratory pressure, 4 cm H2O; fraction of inspired oxygen, 0.4) for 30, 60, 120, and 240 min. Assigned animals were allowed to recover for 2 days after MV. Both pulmonary tissue and plasma interleukin (IL)-1&agr;, IL-1&bgr;, tumor necrosis factor &agr;, IL-6, IL-10, and keratinocyte-derived chemokine levels were measured. Histopathologic appearance of lung tissue was analyzed by light microscopy and electron microscopy. Results:In lung tissue, all measured cytokines and keratinocyte-derived chemokine levels increased progressively with MV duration. Light microscopy showed increased leukocyte influx but no signs of alveolar leakage or albumin deposition. Electron microscopy revealed intact epithelial cell and basement membranes with sporadically minimal signs of partial endothelial detachment. In plasma, increased levels of IL-1&agr;, tumor necrosis factor &agr;, IL-6, and keratinocyte-derived chemokine were measured after MV. In the recovery animals, cytokine levels had normalized and no histologic alterations could be found. Conclusions:Mechanical ventilation induces reversible cytokine increase and leukocyte influx with preserved tissue integrity. This model offers opportunities to study the pathophysiologic mechanisms behind ventilator-induced lung injury and the contribution of MV to the “multiple-hit” concept.

Coronary artery bypass grafting using two different anesthetic techniques: Part 3: Adrenergic responses.

Twenty patients were studied during and after coronary artery bypass grafting (CABG). The patients were randomly assigned to two groups. In 10 patients, intraoperative general anesthesia (GA) was based on a combination of intravenous (IV) sufentanil and midazolam. In 10 other patients, thoracic epidural analgesia (TEA) with 0.375% bupivacaine plus sufentanil, 1:200,000 (5 micrograms/mL), and intraoperative GA with midazolam/N2O were used. During the prebypass period, lower heart rates (HR), less variability in mean arterial pressure (MAP), and systemic vascular resistance (SVR) was accompanied by less variability in plasma norepinephrine (NE) concentrations in the TEA group. Although no differences were observed between the groups in perfusion pressure and the amount of vasoactive drugs used during the bypass period, variability in SVR was less in the TEA group. This was accompanied by less increase in NE and less variability in epinephrine (E) plasma concentrations. However, cortisol (Co) release was higher during this period in the TEA group. Weaning from bypass was accompanied by higher MAP and SVR in the TEA group at a lower HR, whereas no differences were observed in the E, NE, and Co plasma concentrations between the groups. During the first and second postoperative days, better pain relief and lower E and Co plasma concentrations were found in the TEA group. It can be concluded that better hemodynamic stability during the prebypass and bypass periods was accompanied by less E and NE release during these periods. Co release in the TEA group was higher during the bypass period. Weaning from bypass was characterized by better hemodynamics in the TEA group.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys

Background: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic γ-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation. Methods: Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-&mgr;g/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-&mgr;g/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected. Results: Injection of 100 &mgr;g/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 &mgr;g/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate. Conclusions: Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.

Extension of sensory blockade after thoracic epidural administration of a test dose of lidocaine at three different levels

To evaluate the relationship between the level of thoracic epidural injection and the extension of sensory blockade, we inserted radiopaque epidural catheters in 87 patients at the high (C7-T2, n = 28), mid (T3-5, n = 29) or low (T7-9, n = 30) thoracic levels. Fifteen minutes after the epidural administration of 60 mg of lidocaine, the mean (+/- SD) sensory block extension varied from 5.4 +/- 3.1 to 7.7 +/- 1.8 segments. The level of epidural puncture was a statistically significant factor in determining the cranial and caudal borders of sensory blockade (P = 0.0001, analysis of variance), but in determining for the total number of segments blocked. The number of blocked dermatomes located cranially of the puncture level increased significantly with descending injection site (P = 0.0001). We acquired chest radiographs in 61 patients to determine epidural catheter tip position. Direction of the epidural catheter tip was not a significant factor in determining the extension or borders of sensory blockade. We conclude that the extension of sensory blockade in thoracic epidural anesthesia is not influenced by the level of epidural puncture or catheter tip direction. There is, however, a more cranial spread of sensory blockade in the low thoracic region compared with the high thoracic region. Implications: After evaluating the extension and pattern of sensory blockade in high, mid, and low thoracic epidural analgesia, the authors suggest that it is safe to use similar dosage regimens in all three regions, and that in high thoracic epidural analgesia, it is important to insert the epidural catheter at the level of the intended cranial border of blockade. (Anesth Analg 1998;86:332-5)

Isoflurane anesthesia is a valuable alternative for alpha-chloralose anesthesia in the forepaw stimulation model in rats.

Isoflurane (ISO) can be a valuable alternative for α‐chloralose (ACL) anesthesia in functional MRI (fMRI) studies. Therefore, we compared the efficacy of the blood oxygen level dependent (BOLD) effect in fMRI studies during ISO and ACL anesthesia sequentially in the same animals. After non‐invasive instrumentation for ventilation and monitoring, series of T2* weighted MR images were acquired during forepaw stimulation, first under ISO, then followed by ACL anesthesia. The results demonstrated that ISO and ACL were both suitable to perform this fMRI experiment. The center of activation was at the same stereotactic position for both anesthetics and matched the primary somatosensory cortex (S1). Under the applied conditions, the BOLD response during ISO anesthesia declined in magnitude during the first stimulation period, as compared to ACL. From this study, we conclude that since ISO has several positive properties in comparison to ACL, including fast pharmacokinetics and suitability for repeated measurements, it is a valuable alternative for anesthesia in fMRI studies of rats. Copyright

Mechanical ventilation induces a Toll/interleukin-1 receptor domain-containing adapter-inducing interferon beta-dependent inflammatory response in healthy mice.

Background:Mechanical ventilation (MV) can induce lung injury. Proinflammatory cytokines have been shown to play an important role in the development of ventilator-induced lung injury. Previously, the authors have shown a role for Toll-like receptor 4 signaling. The current study aims to investigate the role of Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-&bgr; (TRIF), a protein downstream of Toll-like receptors, in the development of the inflammatory response after MV in healthy mice. Methods:Wild-type C57BL6 and TRIF mutant mice were mechanically ventilated for 4 h. Lung tissue and plasma was used to investigate changes in cytokine profile, leukocyte influx, and nuclear factor-&kgr;B activity. In addition, experiments were performed to assess the role of TRIF in changes in cardiopulmonary physiology after MV. Results:MV significantly increased messenger RNA expression of interleukin (IL)-1&bgr; in wild-type mice, but not in TRIF mutant mice. In lung homogenates, MV increased levels of IL-1&agr;, IL-1&bgr;, and keratinocyte-derived chemokine in wild-type mice. In contrast, in TRIF mutant mice, only a minor increase in IL-1&bgr; and keratinocyte-derived chemokine was found after MV. Nuclear factor-&kgr;B activity after MV was significantly lower in TRIF mutant mice compared with wild-type mice. In plasma, MV increased levels of IL-6 and keratinocyte-derived chemokine. In TRIF mutant mice, no increase of IL-6 was found after MV, and the increase in keratinocyte-derived chemokine appeared less pronounced. TRIF deletion did not affect cardiopulmonary physiology after MV. Conclusions:The current study supports a prominent role for TRIF in the development of the pulmonary and systemic inflammatory response after MV.

Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice

Background:Mechanical ventilation with small tidal volumes reduces the development of ventilator-induced lung injury and mortality, but may increase Paco2. It is not clear whether the beneficial effect of a lung-protective strategy results from reduced ventilation pressures/tidal volumes or is mediated by the effects of hypercapnic acidosis on the inflammatory response involved in the pathogenesis of ventilator-induced lung injury. Objective:To analyze whether hypercapnic acidosis affects lung tissue cytokine levels and leukocyte influx in healthy ventilated mice. Study Design:Analysis of lung tissue and plasma concentrations of interleukin (IL)-1&bgr;, tumor necrosis factor (TNF)-&agr;, IL-6, IL-10, and keratocyte-derived chemokine after 2 hrs of mechanical ventilation (Vt 8 mL/kg, positive end-expiratory pressure 4 cm H2O) with 0.06% CO2 (room air), 2% CO2, or 4% CO2. Subjects:Healthy C57BL6 mice (n = 40). Measurements/Results:Paco2 and pH were within normal range when ventilated with 0.06% CO2 and significantly changed with 2% and 4% CO2: (mean ± sd) pH 7.23 ± 0.06 and 7.15 ± 0.04, Paco2 7.9 ± 1.4 and 10.8 ± 0.7 kPa, respectively (p < 0.005). Blood pressure remained within normal limits in all animals. Quantitative microscopic analysis showed a 4.7 ± 3.7-fold increase (p < 0.01) in pulmonary leukocyte influx in normocapnic ventilated animals and a significant reduction in leukocyte influx of 57 ± 32% (p < 0.01) and 67 ± 22% (p < 0.01) when ventilated with 2% and 4% CO2, respectively. Normocapnic ventilation induced a significant elevation of lung tissue IL-1&bgr; (1516 ± 119 ng/mL), TNF-&agr; (344 ± 88 ng/mL), IL-6 (6310 ± 807 ng/mL), IL-10 (995 ± 152 ng/mL), and keratocyte-derived chemokine (36,966 ± 15,294 ng/mL) (all p-values <0.01). Hypercapnic acidosis with 2% respectively 4% CO2 significantly attenuated this increase with 25 ± 32% and 54 ± 32% (IL-1&bgr;, p < 0.01); 17 ± 36% and 58 ± 33% (TNF-&agr;, p < 0.02); 22 ± 34% and 89 ± 6% (IL-6, p < 0.01); 20 ± 31% and 67 ± 17% (IL-10, p < 0.01) and 16 ± 44% and 45 ± 30% (keratocyte-derived chemokine, p = 0.07). Conclusion:Hypercapnic acidosis attenuates the mechanical ventilation-induced immune response independent from reduced tidal volumes/pressures and may protect the lung from ventilator induced lung injury.

Time-course of action of rocuronium 0.3 mg.kg-1 in children with and without endstage renal failure.

Background: The time‐course of the neuromuscular effects of rocuronium 0.3 mg·kg−1 during nitrous oxide‐halothane anaesthesia in children with and without renal failure is unknown. This study compared the neuromuscular blocking effects in these groups.