Philipp Lirk

The efficacy of preemptive analgesia for acute postoperative pain management : A meta-analysis

Whether preemptive analgesic interventions are more effective than conventional regimens in managing acute postoperative pain remains controversial. We systematically searched for randomized controlled trials that specifically compared preoperative analgesic interventions with similar postoperative analgesic interventions via the same route. The retrieved reports were stratified according to five types of analgesic interventions: epidural analgesia, local anesthetic wound infiltration, systemic N-methyl-d-aspartic acid (NMDA) receptor antagonists, systemic nonsteroidal antiinflammatory drugs (NSAIDs), and systemic opioids. The primary outcome measures analyzed were the pain intensity scores, supplemental analgesic consumption, and time to first analgesic consumption. Sixty-six studies with data from 3261 patients were analyzed. Data were combined by using a fixed-effect model, and the effect size index (ES) used was the standardized mean difference. When the data from all three outcome measures were combined, the ES was most pronounced for preemptive administration of epidural analgesia (ES, 0.38; 95% confidence interval [CI], 0.28–0.47), local anesthetic wound infiltration (ES, 0.29; 95% CI, 0.17–0.40), and NSAID administration (ES, 0.39; 95% CI, 0.27–0.48). Whereas preemptive epidural analgesia resulted in consistent improvements in all three outcome variables, preemptive local anesthetic wound infiltration and NSAID administration improved analgesic consumption and time to first rescue analgesic request, but not postoperative pain scores. The least proof of efficacy was found in the case of systemic NMDA antagonist (ES, 0.09; 95% CI, −0.03 to 0.22) and opioid (ES, −0.10; 95% CI, −0.26 to 0.07) administration, and the results remain equivocal.

An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the integrated role of the COX pathway in the generation of inflammation and in the biochemical recognition of pain. This group of drugs has recently come under scrutiny because of recent focus in the literature on the various adverse effects that can occur when applying NSAIDs. This review will provide an educational update on the current evidence of the efficacy and adverse effects of NSAIDs. It aims to answer the following questions: (1) are there clinically important differences in the efficacy and safety between the different NSAIDs, (2) if there are differences, which are the ones that are more effective and associated with fewer adverse effects, and (3) which are the effective therapeutic approaches that could reduce the adverse effects of NSAIDs. Finally, an algorithm is proposed which delineates a general decision-making tree to select the most appropriate analgesic for an individual patient based on the evidence reviewed.

Mass spectrometric profile of exhaled breath—field study by PTR-MS

Recently, increased interest has focused on the diagnostic potential of volatile organic compounds (VOC) exhaled in human breath as this substance group has been conjectured in indoor air quality and disease screening. Proton transfer reaction-mass spectrometry (PTR-MS) has been established as a new tool for a rapid determination of exhaled air profile. However, no investigations have been carried out into the profile of exhaled air as determined by PTR-MS. Therefore, it was the aim of the present study to determine the profile of exhaled breath in a field survey enrolling 344 persons. Analysis was performed using PTR-MS. No significant correlations with age, blood pressure, and body mass index could be observed with any molecular mass. The present study delineates possible reference values for PTR-MS investigations into exhaled air profile. In conclusion, the present study was the first to delineate mass spectrometric characteristics of an average patient sample as possible reference values.

Failed epidural: causes and management

Failed epidural anaesthesia or analgesia is more frequent than generally recognized. We review the factors known to influence the success rate of epidural anaesthesia. Reasons for an inadequate epidural block include incorrect primary placement, secondary migration of a catheter after correct placement, and suboptimal dosing of local anaesthetic drugs. For catheter placement, the loss of resistance using saline has become the most widely used method. Patient positioning, the use of a midline or paramedian approach, and the method used for catheter fixation can all influence the success rate. When using equipotent doses, the difference in clinical effect between bupivacaine and the newer isoforms levobupivacaine and ropivacaine appears minimal. With continuous infusion, dose is the primary determinant of epidural anaesthesia quality, with volume and concentration playing a lesser role. Addition of adjuvants, especially opioids and epinephrine, may substantially increase the success rate of epidural analgesia. Adjuvant opioids may have a spinal or supraspinal action. The use of patient-controlled epidural analgesia with background infusion appears to be the best method for postoperative analgesia.

Inducible nitric oxide synthase--time for reappraisal.

Inducible nitric oxide synthase (iNOS) is one of three key enzymes generating nitric oxide (NO) from the amino acid L-arginine. iNOS-derived NO plays an important role in numerous physiological and pathophysiological conditions, e.g. blood pressure regulation, inflammation, infection, and the onset and progression of malignant diseases. iNOS has been conjectured both as a marker and a therapeutic target in these situations. iNOS is a mediator of unspecific host defence, central in the clearance of bacterial, viral, fungal and parasitic infections. However, excess production of NO appears to be linked to tissue damage and organ dysfunction, e.g. the hypotensive and vasoplegic state characteristic for septic shock. However, the use of iNOS-inhibitors in septic patients should be performed carefully with regard to the essential functions and properties of NO in blood pressure/blood flow regulation. Considering iNOS-derived NO as a multifactorial transmitter of tumorigenesis and tumor progression, it is tempting to speculate on therapeutical interference with iNOS activity, especially in tumors where metastatic activity, host denfence mechanisms and the level of differentiation seem to be correlated to iNOS expression. It is the aim of this review to provide basic insights into the NOS family of enzymes as well as their regulation. In the second part of the review, we will point out the pivotal roles NOS play in inflammation and neoplastic diseases.

Cervical and High Thoracic Ligamentum Flavum Frequently Fails to Fuse in the Midline

Background Cervical and high thoracic epidural anesthesia and analgesia have gained increasing importance in the treatment of painful conditions and as components of anesthetics for cardiac and breast surgery. In contrast to the hanging-drop technique, the loss-of-resistance technique is thought to rely on the penetration of the ligamentum flavum. However, the exact morphology of the ligamentum flavum at different vertebral levels remains controversial. Therefore, the aim of this study was to investigate the incidence and morphology of cervical and high thoracic ligamentum flavum mid-line gaps in embalmed cadavers. Methods Vertebral column specimens were obtained from 52 human cadavers. On each dissected level, ligamentum flavum mid-line gaps were recorded and evaluated with respect to shape and size. Results The following variations were encountered: complete fusion in the mid-line, mid-line fusion with a gap in the caudal part, mid-line gap, and mid-line gap with widened caudal end. The incidence of mid-line gaps at the following levels was: C3–C4: 66%, C4–C5: 58%, C5–C6: 74%, C6–C7: 64%, C7–T1: 51%, Th1–Th2: 21%, Th2–Th3: 11%, Th3–Th4: 4%, Th4–Th5: 2%, and Th5–Th6: 2%. The mean width of mid-line gaps was 1.0 ± 0.3 mm. Conclusions In conclusion, the present study shows that gaps in the ligamenta flava are frequent at cervical and high thoracic levels but become rare at the T3/T4 level and below, such that one cannot always rely on the ligamentum flavum as a perceptible barrier to epidural needle placement at these levels.

Distinct membrane effects of spinal nerve ligation on injured and adjacent dorsal root ganglion neurons in rats.

Background:Painful peripheral nerve injury results in disordered sensory neuron function that contributes to the pathogenesis of neuropathic pain. However, the relative roles of neurons with transected axons versus intact adjacent neurons have not been resolved. An essential first step is identification of electrophysiologic changes in these two neuronal populations after partial nerve damage. Methods:Twenty days after spinal nerve ligation (SNL), intracellular recordings were obtained from axotomized fifth lumbar (L5) dorsal root ganglion neurons and adjacent, intact L4 neurons, as well as from control neurons and others subjected to sham-SNL surgery. Results:Pronounced electrophysiologic changes were seen only in L5 neurons after SNL. Both Aα/β and A&dgr; neuron types showed increased action potential duration, decreased afterhyperpolarization amplitude and duration, and decreased current threshold for action potential initiation. Aα/β neurons showed resting membrane potential depolarization, and increased repetitive firing during sustained depolarization developed in A&dgr; neurons. The afterhyperpolarization duration in neurons with C fibers shortened after axotomy. In contrast to the axotomized L5 neurons, neighboring L4 neurons showed no changes in action potential duration, afterhyperpolarization dimensions, or excitability after SNL. Depolarization rate (dV/dt) increased after SNL in L4 Aα/β and A&dgr; neurons but decreased in L5 neurons. Time-dependent rectification during hyperpolarizing current injection (sag) was greater after SNL in Aα/β L4 neurons compared with L5. Sham-SNL surgery produced only a decreased input resistance in Aα/β neurons and a decreased conduction velocity in medium-sized cells. In the L5 ganglion after axotomy, a novel set of neurons, consisting of 24% of the myelinated population, exhibited long action potential durations despite myelinated neuron conduction velocities, particularly depolarized resting membrane potential, low depolarization rate, and absence of sag. Conclusions:These findings indicate that nerve injury–induced electrical instability is restricted to axotomized neurons and is absent in adjacent intact neurons.

Failed Obstetric Tracheal Intubation and Postoperative Respiratory Support with the ProSeal™ Laryngeal Mask Airway

UNLABELLED The ProSeal laryngeal mask airway (ProSeal LMA) provides a better seal and probably better airway protection than the classic laryngeal mask airway (classic LMA). We report the use of the ProSeal LMA in a 26-yr-old female with HELLP syndrome for failed obstetric intubation and postoperative respiratory support. Both laryngoscope-guided tracheal intubation and face mask ventilation failed, but a size 4 ProSeal LMA was easily inserted and high tidal volumes obtained. A gastric tube was inserted through the ProSeal LMA drain tube and 300 mL of clear fluid was removed from the stomach. There were no hemodynamic changes during ProSeal LMA insertion. Postoperatively, the patient was transferred to the intensive care unit, where she was ventilated via the ProSeal LMA for 8 h until the platelet count had increased and she was hemodynamically stable. Weaning and ProSeal LMA removal were uneventful. There is anecdotal evidence supporting the use of the LMA devices for failed obstetric intubation (19 cases) and for postoperative respiratory support (8 cases). In principle, the ProSeal LMA may offer some advantages over the classic LMA in both these situations. IMPLICATIONS We report the successful use of the ProSeal laryngeal mask airway for failed obstetric intubation and postoperative respiratory support in a patient with HELLP syndrome.

Lidocaine time- and dose-dependently demethylates deoxyribonucleic acid in breast cancer cell lines in vitro

BACKGROUND Anaesthetic management of cancer surgery may influence tumour recurrence. The modulation of gene expression by methylation of deoxyribonucleic acid (DNA) (epigenetics) is increasingly recognized as a major hallmark of cancer. Next to direct effects of local anaesthetics upon tumour cells, the ester-type local anaesthetic, procaine, has been shown to affect methylation status in several tumour cell lines, promoting the reactivation of tumour suppressor genes. We sought to determine whether the prototype amide-type local anaesthetic, lidocaine, influences the survival and epigenetic status of oestrogen receptor (ER)-positive and -negative breast cancer cell lines in vitro. METHODS Breast cancer cell lines BT-20 (ER-negative) and MCF-7 (ER-positive) were incubated with lidocaine and procaine as the reference substance. We performed cell count and determined apoptosis using TUNEL stain. Further, we assessed global methylation status, and methylation of three known tumour suppressor genes (RASSF1A, MYOD1, and GSTP1) using the MethyLight assay and real-time quantitative polymerase chain reaction, respectively. RESULTS Baseline methylation was 100-fold higher in BT-20 cells. Here, we observed a dose-dependent decrease in DNA methylation in response to lidocaine (1, 0.01, and 0.01 mM) after 72 h (P<0.001, <0.001, and 0.004, respectively). The corresponding changes were smaller in MCF-7 cells. Global methylation status was profoundly influenced, but the methylation and mRNA expression status of three tumour suppressor genes was unchanged. CONCLUSIONS Our findings suggest that demethylating tumour-suppressive effects of anaesthetic interventions may only be detectable in specific types of cancer due to differential methylation profiles. In conclusion, at clinically relevant concentrations, lidocaine demethylates DNA of breast cancer cell lines in vitro.

In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity.

BACKGROUND:Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses that these drugs (A) are less neurotoxic than the prototype local anesthetic, lidocaine (B) are selectively toxic for subcategories of dorsal root ganglion neurons and (C) induce activation of either p38 MAPK or related enzymes, such as the c-jun terminal N-kinase (JNK) and extracellular signal-regulated kinase (ERK). METHODS:We incubated primary sensory neuron cultures with doses of lidocaine, bupivacaine, and ropivacaine equipotent at blocking sodium currents. Next, we sought to determine potential selectivity of bupivacaine and ropivacaine toxicity on neuron categories defined by immunohistochemical staining, or size. Subsequently, the involvement of p38 MAPK, JNK, and ERK was tested using enzyme-linked immunosorbent assays. Finally, the relevance of MAPK pathways in bupivacaine- and ropivacaine-induced neurotoxicity was determined by selectively inhibiting activity of p38 MAPK, JNK, and ERK. RESULTS:We found that the neurotoxic potency of bupivacaine and ropivacaine is dose-dependent and similar in vitro, but is not selective for any of the investigated subgroups of neurons. Neurotoxicity of bupivacaine and ropivacaine was mediated, at least in part, by MAPKs. Specifically, we demonstrated the relevance of both p38 MAPK and JNK pathways for the neurotoxicity of bupivacaine and characterized the involvement of the p38 MAPK pathway in the neurotoxicity of ropivacaine. CONCLUSIONS:Given equipotent doses, the neurotoxic potential of lidocaine does not appear to be significantly different from that of bupivacaine and ropivacaine in vitro. Moreover, bupivacaine and ropivacaine do not exert their neurotoxicity differently on specific subsets of dorsal root ganglion neurons. Their neurotoxic effects are brought about through the activation of specific MAPKs; the specific pharmacologic inhibition of these kinases attenuates toxicity in vitro.