Ralph-Thomas Kiefer

Efficacy of Ketamine in Anesthetic Dosage for the Treatment of Refractory Complex Regional Pain Syndrome: An Open‐Label Phase II Study

OBJECTIVE Advanced complex regional pain syndrome (CRPS) remains very difficult to treat. While subanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advanced CRPS has not been as effective. Since ketamines analgesic potency and duration of effect in neuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anesthetic dosage in refractory CRPS patients that had failed available standard therapies. METHODS Twenty ASA I-III patients suffering from refractory CRPS received ketamine in anesthetic dosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality of life, and ability to work at baseline and up to 6 months following treatment. RESULTS Significant pain relief was observed at 1, 3, and 6 months following treatment (93.5 +/- 11.1%, 89.4 +/- 17.0%, 79.3 +/- 25.3%; P < 0.001). Complete remission from CRPS was observed at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapse occurred, significant pain relief was still attained at 3 and 6 months (59.0 +/- 14.7%, P < 0.004; 50.2 +/- 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to work significantly improved in the majority of patients at 3 and 6 months. CONCLUSIONS This open-label trial suggests benefit in pain reduction, associated CRPS symptoms, improved quality of life and ability to work following anesthetic ketamine in previously refractory CRPS patients. However, a randomized controlled trial will be necessary to prove its efficacy.

Complete Recovery From Intractable Complex Regional Pain Syndrome, CRPS-Type I, Following Anesthetic Ketamine and Midazolam

Objective: To describe the treatment of an intractable complex regional pain syndrome I (CRPS‐I) patient with anesthetic doses of ketamine supplemented with midazolam.

A Pilot Open-Label Study of the Efficacy of Subanesthetic Isomeric S( + )-Ketamine in Refractory CRPS Patients

OBJECTIVE Complex regional pain syndrome (CRPS) is a severe neuropathic pain state that is often disproportionate to the initial trauma. Associated features are autonomic dysregulation, swelling, motor dysfunction, and trophic changes to varying degrees. Despite a multitude of treatment modalities, a subgroup of CRPS patients remain refractory to all standard therapies. In these patients, the disease may spread extraterritorially, which results in severe disability. A critical involvement of N-methyl-D-aspartate receptors (NMDARs) has been demonstrated both clinically and by animal experimentation. NMDA antagonists may be effective in many neuropathic pain states. In long-standing, generalized CRPS, we investigated the effects of S(+)-ketamine on pain relief and somatosensory features, assessed by quantitative sensory testing (QST). METHODS Four refractory CRPS patients received continous S(+)-ketamine-infusions, gradually titrated (50 mg/day-500 mg/day) over a 10-day period. Pain intensities (average, peak, and least pain) and side effects were rated on visual analogue scales, during a 4-day baseline, over 10 treatment days, and 2 days following treatment. QST (thermo-, mechanical detection, and pain thresholds) was analyzed at baseline and following treatment. RESULTS Subanesthetic S(+)-ketamine showed no reduction of pain and effected no change in thermo- and mechanical detection or pain thresholds. This procedure caused no relevant side effects. The lack of therapeutic response in the first four patients led to termination of this pilot study. CONCLUSION S(+)-ketamine can be gradually titrated to large doses (500 mg/day) without clinically relevant side effects. There was no pain relief or change in QST measurements in this series of long-standing severe CRPS patients.

Local anesthetics impair human granulocyte phagocytosis activity, oxidative burst, and CD11b expression in response to Staphylococcus aureus.

Background With invasion of bacteria, the host defense system is activated by a complex cascade of various mechanisms. Local anesthetics previously were shown to interact with diverse components of the immune response, such as leukocyte adherence on endothelial monolayers, oxidative burst, or crosstalk within lymphocyte subset populations. However, effects of newer local anesthetics like bupivacaine and ropivacaine on antibacterial host defense—primarily phagocytosis activity, oxidative burst, or CD11b expression—still remain unclear. Methods Whole blood samples were preincubated with local anesthetics (lidocaine, 9.2, 92.2, and 1,846 &mgr;m; bupivacaine, 6.1, 61, and 770 &mgr;m; ropivacaine, 6.4, 64, and 801 &mgr;m). For the oxidative burst and CD11b assay, dihydroethidium was added to the probes. After viable Staphylococcus aureus was added in a 5 to 1 ratio following leukocyte count, phagocytosis was stopped at different times, and staining with monoclonal antibodies was performed for subsequent flow cytometric analysis of phagocytosis activity, oxidative burst, and CD11b expression. Results Granulocyte phagocytosis activity, CD11b expression, and generation of reactive oxygen species were significantly reduced by lidocaine (P < 0.0002) and bupivacaine (P < 0.005) in the highest concentration (1,846 &mgr;m and 770 &mgr;m, respectively). The capability of granulocytes to ingest bacteria was significantly depressed only by lidocaine (P < 0.003). Ropivacaine had no significant effect on any parameter investigated. Conclusions Local anesthetic dose and structure dependently inhibit inflammatory and immunologic parameters of granulocyte functions. Ropivacaine shows low interference with granulocyte immunologic and inflammatory functions.

Low-dose oral clonidine as premedication before intraocular surgery in retrobulbar anesthesia

PURPOSE We investigated whether low-dosed oral clonidine premedication before elective intraocular surgery in retrobulbar anesthesia is effective in terms of anxiolysis, sedation, stable hemodynamics, lower intraocular pressure and perioperative endocrine stress response. METHODS In a prospective, randomised, double-blind study, 44 patients scheduled for elective intraocular surgery received either 0.15 mg clonidine (n=22) or a matched placebo (n=22) orally 60 minutes before retrobulbar anesthesia. The main study parameters were sedation, anxiolysis, hemodynamics and intraocular pressure. Additionally, mediators of endocrine stress responses were measured five times, in 13 patients after clonidine and 12 after placebo. RESULTS After clonidine 86% of the patients showed sedation and after placebo 90.9% showed no sedation (p<0.01). Clonidine produced effective anxiolysis (Erlanger-Anxiety-Scale: 31.6 +/- 2.6 points vs. 38.1 +/- 8.5 points) before the operation (p<0.01). Systolic blood pressure was significantly lower after clonidine. Effects on mean and diastolic blood pressure were small but statistically significant. Norepinephrine and cortisol plasma concentrations were significantly lower after clonidine. Intraocular pressure was significantly lower too (p<0.05). No clinically relevant adverse effects were observed e.g. inappropriate sedation, hypotension (<100 mmHg), bradycardia (<50 bpm) or hypoxemia (SpO2<90%). CONCLUSIONS Oral low-dose clonidine produces light sedation, significant anxiolysis and stable hemodynamics, and attenuates the endocrine response to perioperative stress. Thus, clonidine seems sufficient to increase patient comfort for intraocular surgery and might even offer clinically worthwhile benefits such as stable hemodynamics and a reduced response to perioperative stress.

Local anesthetic effects on human neutrophil priming and activation.

Background: The anti-inflammatory effects of local anesthetics (LAs) are well documented. Local anesthetics in micromolar concentrations inhibit extracellular oxygen release in isolated neutrophils; the underlying mechanism seems to be an inhibition of leukocyte priming. It remains unclear, however, if first, these effects also can be observed in whole blood, and second, if the priming of other neutrophil functions is similarly attenuated by LAs. Furthermore, the effects of LAs on intracellular generation of oxidative species remain to be investigated. Methods: Whole-blood samples from healthy volunteers were incubated for 0, 1, or 3 hrs with different concentrations (10−7 to 10−4 M) of either lidocaine, ropivacaine, QX314, or NaCl 0.9% as control. Dihydroethidium was added to quantify oxidative burst. Samples were primed with platelet-activating factor (PAF, 10−5 M) and/or activated with formyl-methyl-leucyl-phenylalanine (10−5 M) for 15 mins each. After staining for CD11b and lysis of erythrocytes, samples were analyzed by flow cytometry. Results: Priming of leukocytes is a relevant mechanism in whole blood. Platelet-activating factor stimulates the priming of oxidative burst and CD11b expression. Lidocaine up to millimolar concentrations did not affect the PAF priming and formyl-methyl-leucyl-phenylalanine activation of oxidative burst. The priming of CD11b expression and the priming and activation of changes in cell morphology were significantly attenuated by lidocaine. Conclusions: The intracellular generation of reactive oxygen species remains largely unaffected by LAs in clinical concentrations. This suggests that the anti-inflammatory effects of LAs do not interfere with the host defense.

Local Anesthetics Time-Dependently Inhibit Staphylococcus aureus Phagocytosis, Oxidative Burst and CD11b Expression by Human Neutrophils

Background and Objectives: Local anesthetics have been shown to modulate neutrophil functions in a time‐dependent manner, which might help to prevent inflammatory injury to the organism. However, if host defense mechanisms are affected similarly, the ability to eliminate bacteria might be reduced. We hypothesized that local anesthetics have time‐dependent effects on phagocytosis of S. aureus, oxidative burst, and CD11b expression by human neutrophils. To test this hypothesis, we reanalyzed data from a previous study. Methods: Blood samples from 11 healthy volunteers were incubated with lidocaine (1,846 &mgr;mol/L), bupivacaine (770 &mgr;mol/L) or ropivacaine (801 &mgr;mol/L) for 30 minutes. Thereafter, bacteria were added, either fluorescently labeled for determination of phagocytosis, or unstained for determination of oxidative burst and CD11b expression. After an additional incubation for 0, 10, 30, or 60 minutes, phagocytosis was stopped and neutrophils were stained with monoclonal antibodies for flow cytometric analysis. Data were analyzed by analysis of variance for repeated measurements. Results: Lidocaine and bupivacaine inhibited neutrophil functions in a time‐dependent manner (P < .05). Prolonged local anesthetic exposure reduced the fraction of ingesting neutrophils by 20% ± 12% (mean ± SD) and 7% ± 7%, bacterial uptake by 19% ± 16% and 14% ± 12%, oxidative burst by 29% ± 23% and 28% ± 25%, and CD11b expression by 66% ± 24% and 25% ± 21% for lidocaine and bupivacaine, respectively. Ropivacaine exerted a time‐dependent effect on CD11b expression only (24% ± 34%; P < .05). Conclusions: Our results indicate that in a whole blood model, time‐dependent effects of local anesthetics affect key neutrophil functions necessary for bacterial elimination. However, these effects only occur at concentrations that are unlikely to be routinely attained in the clinical setting, and concern about interfering with the host defense is likely unwarranted.

Monocyte Phagocytosis of Viable Staphylococcus aureus is Impaired by Barbiturates, but not by Propofol

Background:Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus.Materials and Methods:Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity.Results:Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 ×10-3 M thiopental or 1.1 × 10-3 M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was8.4 × 10-3 M for monocyte recruitment and 8.6 × 10-3 M for phagocytosis activity. The corresponding values for methohexital were 4.1 × 10-3 M and 1.1 × 10-3 M, respectively.Conclusion:The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.

Phantom limb pain: a report of two cases

The efficacy of pre‐emptive analgesia for phantom limb pain is still unclear. It is generally accepted that pre hyphen;amputation pain increases the incidence of phantom and stump pain, even if pre‐emptive analgesia is performed before and during surgery and in the postoperative period. Two cases of traumatic upper limb amputations are described here with no pre‐existing pain. Both received similar antinociceptive treatment by continuous block of the brachial plexus through infusion of ropivacaine 0.375% at 5 ml/h for 10 days. Treatment of case 1 was initiated immediately after surgery; however, this amputee developed intensive phantom limb pain which persisted at 6 months. Early use of the prosthesis after surgery was not possible for this patient. The intensity of phantom limb pain in case 2 decreased significantly after 6 months, even though brachial plexus blockade was not started until 5 weeks post‐trauma. This patient used a functional prosthesis intensively beginning early after amputation. Serial magnetoencephalographic recordings were performed in both patients. Only case 2 showed significant changes of cortical reorganization. In case 1 markedly less cortical plasticity was found. A combination of relevant risk factors such as a painful neuroma, behavioural and cognitive coping strategies and the early functional use of prostheses are discussed as important mechanisms contributing to the development of phantom pain and cortical reorganization.

The analgesic potency of NMDA-antagonists--a question of mechanism-based use and timing?

We would like to contribute to the discussion of the excellent work by Nikolajsen et al. (1), a well designed and carefully conducted study of the effect of a memantine on neuropathic pain after amputation or surgery. The authors concluded that memantine at a dosage of 20 mg/d does not reduce spontaneous nor evoked pain inpatients with nerve injury pain. Successful treatment of chronic neuropathic pain remains difficult; often insufficient pain relief is achieved (2,3). However, subjects of Nikolajsen et al. (1) were patients with established chronic pain (duration between 1–28 yr). Data, suggesting a clinical role of N-methyl-d-aspartate (NMDA)-antagonists in chronic neuropathic pain are so far mainly based on single cases or a small series of patients and the use of ketamine (4 –5). The exact clinical role of NMDA-blockade remains to be investigated (2,3,6,7). Strong experimental evidence points at a substantial role of the NMDA-receptor initiating central sensitization possibly leading to persistent pain-states (2,3,6 – 8). Consecutively, the use of NMDA-receptor antagonists in the early postinjury phase, or even before, may blunt or even preempt central sensitization and the subsequent development of chronic pain. From this point of view, the therapeutic efficacy of NMDA-antagonists once chronic pain is established seems to be questionable (2,3).