Andrea Paris

Dexmedetomidine in anaesthesia.

Purpose of review The development of dexmedetomidine, a potent and highly selective α2-adrenoceptor agonist, has created new interest in the use of α2-adrenoceptor agonists, and has led to its evaluation in various yet non-approved perioperative settings. The current review focuses on the usefulness of dexmedetomidine in anaesthesia practice. Recent findings Recently acquired knowledge and experience with dexmedetomidine in perioperative use will be presented and discussed in the context of known pharmacological properties. Summary Dexmedetomidine offers beneficial pharmacological properties, providing dose-dependent sedation, analgesia, sympatholysis and anxiolysis without relevant respiratory depression. The side-effects are predictable from the pharmacological profile of (2-adrenoceptor agonists. In particular, the unique sedative properties of dexmedetomidine resulted in several interesting applications in anaesthesia practice, promising benefits in the perioperative use of this compound. However, dexmedetomidine was approved for sedation in the intensive care unit in the USA in 1999, and administration in anaesthesia practice remains an ‘off-label’ use. Further studies are needed to establish the role of dexmedetomidine in the perioperative period.

Neuroendocrine stress response and heart rate variability: a comparison of total intravenous versus balanced anesthesia.

Attenuating intraoperative stress is a key factor in improving outcome. We compared neuroendocrine changes and heart rate variability (HRV) during balanced anesthesia (BAL) versus total IV anesthesia (TIVA). Forty-three patients randomly received either BAL (sevoflurane/remifentanil) or TIVA (propofol/remifentanil). Depth of anesthesia was monitored by bispectral index. Stress hormones were measured at 7 time points (P1 = baseline; P2 = tracheal intubation; P3 = skin incision; P4 = maximum operative trauma; P5 = end of surgery; P6 = tracheal extubation; P7 = 15 min after tracheal extubation). HRV was analyzed by power spectrum analysis: very low frequency (VLF), low frequency (LF), high frequency (HF), LF/HF ratio, and total power (TP). LF/HF was higher in TIVA at P6 and TP was higher in TIVA at P3–7 (P3: 412.6 versus 94.2; P4: 266.7 versus 114.6; P5: 290.3 versus 111.9; P6: 1523.7 versus 658.1; P7: 1225.6 versus 342.6 ms2). BAL showed higher levels of epinephrine (P7: 100.5 versus 54 pg/mL), norepinephrine (P3: 221 versus 119.5; P4: 194 versus 130.5 pg/mL), adrenocorticotropic hormone (P2 10.5 versus 7.7; P5: 5.3 versus 3.6; P6: 10.9 versus 5.3; P7: 20.5 versus 7.1 pg/mL) and cortisol (P7: 6.9 versus 3.9 &mgr;g/dL). This indicates a higher sympathetic outflow using BAL versus TIVA during ear-nose-throat surgery.

Sevoflurane but not propofol preserves myocardial function during minimally invasive direct coronary artery bypass surgery.

Volatile anesthetics exert cardioprotective properties in experimental and clinical studies. We designed this study to investigate the effects of sevoflurane on left ventricular (LV) performance during minimally invasive direct coronary artery bypass grafting (MIDCAB) without cardiopulmonary bypass. Fifty-two patients scheduled for MIDCAB surgery were randomly assigned to a propofol or a sevoflurane group. Apart from the anesthetics used, there was no difference in surgical and anesthetic management. After determination of cardiac troponin T, creatine kinase, and creatine kinase MB, electrocardiographic (ECG) data and echocardiography variables (myocardial performance index and early to atrial filling velocity ratio) the left anterior descending coronary artery (LAD) was clamped until anastomosis with the left internal mammary artery was completed. During LAD occlusion and during reperfusion, echocardiography measurements were repeated. Blood samples were obtained repeatedly for up to 72 h. After LAD occlusion, myocardial performance index and early to atrial filling velocity ratio in the propofol group deteriorated significantly from 0.40 ± 0.12 and 1.29 ± 0.35 to 0.49 ± 0.10 and 1.13 ± 0.22, respectively, whereas there was no change in the sevoflurane group. In the propofol group myocardial performance index remained increased (0.47 ± 0.11) compared with baseline during reperfusion. There were no significant differences in ECG and laboratory values between groups. In conclusion, during a brief period of ischemia in patients undergoing MIDCAB surgery, sevoflurane preserved myocardial function better than propofol.

The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype.

We performed the current study in mice lacking individual α2-adrenoceptor subtypes to elucidate the contribution of α2-adrenoceptor subtypes to the neuroprotective properties of dexmedetomidine in a model of perinatal excitotoxic brain injury. On postnatal Day 5, wild-type mice and mice lacking α2A-adrenoceptor (α2A-KO) or α2C-adrenoceptor subtypes (α2C-KO) were randomly assigned to receive dexmedetomidine (3 &mgr;g/kg) or phosphate-buffered saline intraperitoneally. Thirty minutes after the intraperitoneal injection, the glutamatergic agonist ibotenate (10 &mgr;g) was intracerebrally injected, producing transcortical necrosis and white matter lesions that mimic perinatal human hypoxic-like lesions. Quantification of the lesions was performed on postnatal Day 10 by histopathologic examination. Dexmedetomidine reduced mean lesion size in the cortex of wild-type mice and α2C-KO mice by 44% and 49%, respectively. Ibotenate-induced white matter lesions were reduced by 71% (wild-type mice) and 75% (α2C-KO mice) after pretreatment with dexmedetomidine. In contrast, in α2A-KO mice, dexmedetomidine did not protect against the cortical excitotoxic insult, and white matter lesions were even more pronounced (82% increase of mean lesion size). Dexmedetomidine provides potent neuroprotection in a model of perinatal excitotoxic brain damage. This effect was completely abolished in α2A-KO mice, suggesting that the neuroprotective effect is mediated via the α2A-adrenoceptor subtype.

Activation of α2B-Adrenoceptors mediates the cardiovascular effects of etomidate

Background The intravenous anesthetic etomidate exhibits structural similarities to specific &agr;2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with &agr;2-adrenoceptors in mice lacking individual &agr;2-adrenoceptor subtypes (&agr;2-KO). Methods Sedative and cardiovascular responses to etomidate and the &agr;2-agonist, dexmedetomidine, were determined in mice deficient in &agr;2-receptor subtypes. Inhibition of binding of the &agr;2-receptor antagonist [3H]RX821002 to recombinant &agr;2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro. Results In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in &agr;2A-receptor–deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the &agr;2A-receptor subtype. Intravenous injection of etomidate resulted in a transient increase (duration 2.4 ± 0.2 min) in arterial blood pressure in wild-type mice (17 ± 3 mmHg). Etomidate did not affect blood pressure in &agr;2B-KO or &agr;2AB-KO mice. In membranes from HEK293 cells transfected with &agr;2-receptors, etomidate inhibited binding of the &agr;2-antagonist, [3H]RX821002, with higher potency from &agr;2B- and &agr;2C-receptors than from &agr;2A-receptors (Ki &agr;2A 208 &mgr;m , &agr;2B 26 &mgr;m, &agr;2C 56 &mgr;m). In &agr;2B-receptor–expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2. Conclusions These results indicate that etomidate acts as an agonist at &agr;2-adrenoceptors, which appears in vivo primarily as an &agr;2B-receptor–mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.

Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors.

Background:Dexmedetomidine is a potent and selective α2-adrenoceptor (α2AR) agonist that exhibits a broad pattern of actions, including sedation, analgesia, and neuroprotection. Recent studies have emphasized the role of phosphorylated extracellular signal–regulated protein kinases (pERK1 and 2) in coupling rapid events such as neurotransmitter release and receptor stimulation long-lasting changes in synaptic plasticity and cell survival. Here, the authors hypothesized that dexmedetomidine increases pERK1 and 2 content and examined the mechanisms involved in this effect. Methods:The effects of dexmedetomidine and their sensitivity to various pharmacologic agents on expression of pERK1 and 2 were studied by Western blots in hippocampal slices obtained from rats, wild-type mice, and mice carrying targeted deletions of the α2AR subtypes. Results:Dexmedetomidine induced a concentration-related increase in the expression of pERK1 and 2 in rat hippocampal slices (EC50 [95% confidence interval] for pERK1, 0.97 [0.68–1.37] &mgr;m; for pERK2, 1.15 [0.62–2.14] &mgr;m). This effect was insensitive to the inhibitors of the α2AR-mediated signaling pathway, to prazosin, and to PP2, an inhibitor of the focal adhesion kinase–Src kinases. In contrast, it was still present in mice deleted for each of the α2AR subtypes and was markedly decreased by the antagonist of the I1-imidazoline receptors efaroxan, by phospholipase C and protein kinase C inhibitors, and by PD 098059, a direct inhibitor of ERK1 and 2 phosphorylation. Conclusion:Dexmedetomidine increases the expression of pERK1 and 2 via mechanisms independent of α2AR activation. The I1-imidazoline receptors likely contribute to these effects. The results may be relevant to some long-term effects (e.g., neuroprotective) of dexmedetomidine in the brain.

Sedation and analgesia in the intensive care unit.

Purpose of review Sedation and analgesia are important means of providing care for the critically ill patient. Recent findings It is now clear that posttraumatic stress disorders resulting from an intensive care unit stay may be prevented by the right level of sedation. New drug developments but also recent findings in new ventilation strategies allow for a sedation management that is better tailored to an individuals need. Most importantly, regular definition of the appropriate level of sedation and analgesia as well as monitoring of the desired level will help to avoid over- and undersedation and may ultimately improve the outcome of the patient and reduce costs. Summary Sedation and analgesia are now regarded as an integral part of treatment on the intensive care unit instead of being an unpleasant but necessary and minor issue. The importance of monitoring the level of sedation and analgesia has only recently been realized. It remains to be shown that new management strategies including an evaluation of the patient, planned interventions and the choice of drugs will further improve the care for the critically ill.

Effects of clonidine and midazolam premedication on bispectral index and recovery after elective surgery

Background and objectives Alpha-2 agonists offer useful effects that make these drugs an interesting alternative for pharmacological premedication. Methods In a randomized, double-blind study, effects of clonidine (150 μg orally), midazolam (7.5 mg orally) and placebo administered 60–90 min prior to estimated anaesthesia induction time were investigated in 60 healthy ASA I or II patients. All patients received dipotassiumchlorazepate the evening before surgery. At predefined time points, effects of premedication on bispectral index, sedation score and visual analogue scales for anxiety and pain, cognitive function and stress hormones were determined. Results Administration of low-dose clonidine was associated with slightly lower bispectral index scores than a standard dose of midazolam or placebo. There were no significant differences in sedation score, visual analogue scale for anxiety and pain and cognitive function between treatment regimens. Clonidine, but not midazolam, reduced anaesthetic requirements for induction of anaesthesia and prevented an increase in heart rate as well as an increase in adrenocorticotropic hormone plasma levels during the preoperative period (P < 0.05 vs. placebo). Clonidine administration did not delay postoperative recovery. Conclusion Clonidine augmented haemodynamic stability and partially blunted stress responses as determined by adrenocorticotropic hormone plasma levels. In addition, clonidine did not delay postoperative recovery. Therefore, surrogate parameters indicate that preanaesthetic medication with clonidine may be superior to midazolam in healthy individuals. Further studies have to confirm these results with regard to outcome parameters.

The Effect of Meperidine on Thermoregulation in Mice: Involvement of ??2-Adrenoceptors

Meperidine has potent antishivering properties. The underlying mechanisms are not fully elucidated, but recent investigations suggest that &agr;2-adrenoceptors are likely to be involved. We performed the current study to investigate the effects of meperidine on nonshivering thermogenesis in a model of thermoregulation in mice. After injection (0.1 mL/kg intraperitoneally) of saline, meperidine (20 mg/kg), the specific &agr;2-adrenoceptor antagonist atipamezole (2 mg/kg), plus saline or atipamezole plus meperidine, respectively, mice were positioned in a Plexiglas chamber. Rectal temperature and mixed expired carbon dioxide were measured after provoking thermoregulatory effects by whole body cooling. Maximum response intensity of nonshivering thermogenesis and the thermoregulatory threshold for nonshivering thermogenesis, which was defined as the temperature at which a sustained increase in expiratory carbon dioxide can be measured, were investigated. Meperidine significantly decreased the threshold of nonshivering thermogenesis (36.6°C ± 0.7°C) versus saline (37.9°C ± 0.6°C) and versus atipamezole plus saline (37.8°C ± 0.4°C; P < 0.01). This effect was abolished after administration of meperidine combined with atipamezole (37.7°C ± 0.6°C; P < 0.05). Meperidine did not decrease the maximum intensity of nonshivering thermogenesis. The results suggest a major role of &agr;2-adrenoceptors in the inhibition of thermoregulation by meperidine in mice.

Induced arterial hypotension for interventional thoracic aortic stent-graft placement: impact on intracranial haemodynamics and cognitive function

Background and objective: The study investigated the impact of induced arterial hypotension for the facilitation of endovascular stent-graft placement in patients with thoracic aortic aneurysm on cerebral blood flow velocity and neurological/neurocognitive outcome. Methods: In 27 ASA III patients, cerebral blood flow velocity was recorded during induced arterial hypotension for endovascular stent-graft placement using transcranial Doppler sonography and the Folstein Mini Mental State Examination and the National Institute of Health Stroke Scale were performed before and after the intervention. Results: Mean arterial pressure was decreased <50 mmHg, and in 22 patients it was <40 mmHg. Diastolic cerebral blood flow velocity decreased by 59%. Postoperatively, six of 21 patients exhibited changes in the Folstein Mini Mental State Examination and four of these six patients in the National Institute of Health Stroke Scale as indices of new-found neurocognitive dysfunction, but there were no signs of stroke. Loss of the diastolic blood flow profile was detected in two of six patients with new-found neurocognitive dysfunctions and in 18 of 21 patients with no new-found neurocognitive dysfunction. Changes in the Folstein Mini Mental State Examination on postoperative day 1 were correlated to the pre-procedural Folstein Mini Mental State Examination, but not to the time spent with a mean arterial pressure <50 mmHg, <40 mmHg or with a loss of diastolic blood flow profile. Conclusions: Transcranial Doppler sonography visualizes the individual effect of induced hypotension and the period of intracranial circulatory arrest during aortic stent-graft placement. However, transient new-found neurocognitive dysfunctions occur independently of the transcranial Doppler data, and are in close correlation to the neurocognitive state before the procedure. The results suggest that induced arterial hypotension is not the major factor for postoperative new-found neurocognitive dysfunction.