Late preconditioning is blocked by racemic ketamine, but not by S(+)-ketamine

Racemic ketamine blocks K(ATP) channels in isolated cells and abolishes short-term cardioprotection against prolonged ischemia. We investigated the effects of racemic ketamine and S(+)-ketamine on ischemic late preconditioning (LPC) in the rabbit heart in vivo. A coronary occluder was chronically implanted in 36 rabbits. After recovery, the rabbits divided into four groups (each n = 9). LPC was induced in conscious rabbits by a 5-min coronary occlusion. Twenty-four hours later, the animals were instrumented for measurement of left ventricular systolic pressure (LVSP, tip manometer), cardiac output (CO, ultrasonic flowprobe) and myocardial infarct size (triphenyltetrazolium staining). All rabbits were then subjected to 30-min coronary occlusion and 2 h reperfusion. Controls underwent the ischemia-reperfusion program without LPC. To test whether racemic ketamine or S(+)-ketamine blocks the cardioprotection induced by LPC, the drugs (10 mg/kg) were given 10 min before the 30-min ischemia. Hemodynamic values were not significantly different between groups during the experiments (baseline: LVSP, 94 +/- 3 mm Hg [mean +/- SEM] and CO, 243 +/- 9 mL/min; coronary occlusion: LVSP, 93% +/- 4% of baseline and CO, 84% +/- 4%; after 2 h of reperfusion: LVSP, 85% +/- 4% and CO, 83% +/- 4%). LPC reduced infarct size from 44% +/- 3% of the area at risk in controls to 22% +/- 3% (P = 0.002). Administration of racemic ketamine abolished the cardioprotective effects of LPC (44 +/- 4%, P = 0.002). S(+)-ketamine did not affect the infarct size reduction induced by LPC (26 +/- 6%, P = 0.88). IMPLICATIONS: Racemic ketamine, but not S(+)-ketamine, blocks the cardioprotection induced by ischemic late preconditioning in rabbit hearts in vivo. Thus, the influence of ketamine on ischemic late preconditioning is most likely enantiomer specific, and the use of S(+)-ketamine may be preferable in patients with coronary artery disease.     

S(+)-ketamine, but not R(-)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts.

Polymorphonuclear neutrophils (PMN) play a crucial role in the initiation of reperfusion injury. In a previous study, we found that ketamine reduced the postischemic adherence of PMN to the intact coronary system of isolated guinea pig hearts. Because ketamine is a racemic mixture (1:1) of two optical enantiomers, we looked for possible differences in action between the stereoisomers. Seventy-six guinea pig hearts were perfused in the "Langendorff" mode under conditions of constant flow (5 mL/min) using modified Krebs-Henseleit buffer. After 15 min of global warm ischemia, freshly isolated human PMN (10(6)) were infused as a bolus into the coronary system during the second minute of reperfusion. PMN adhesion was expressed as the numeric difference between PMN recovered in the effluent and those applied. Series A hearts received 5 microM S(+), 5 microM R(-), or 10 microM racemic ketamine starting 20 min before ischemia and during reperfusion. In Series B hearts, 10 microM nitro-L-arginine, an inhibitor of NO synthase, was added to the perfusate. In Series C, PMN were preincubated for 15 min with 5 microM S(+)- or R(-)-ketamine. Coronary vascular leak was assessed by measuring the rate of formation of transudate on the epicardial surface. Ischemia/reperfusion without anesthetics increased coronary PMN adherence from 25.5% +/-2.3% (basal) to 35.3%+/-1.5% of the number applied. S(+)-ketamine reduced postischemic adherence in each series (A, 25.5%+/-5.1%; B, 22.5%+/-1.7%; C, 25.3%+/-7.7%), as did racemate (A, 26.4%+/-3.7%). Although 5 microM R(-)-ketamine had no effect on adhesion (A, 30.5%+/-6.7%; B, 34.3%+/-5.1%; C, 34.3%+/-4.3%), it significantly increased vascular leak in the presence of NOLAG. These findings indicate stereoselective differences in biological action between the two ketamine isomers: S(+)-ketamine inhibited PMN adherence, R(-)-ketamine worsened coronary vascular leak in reperfused isolated hearts. IMPLICATIONS: In this study, we demonstrated stereoselective differences in the biologic action of the two ketamine isomers in an animal model of myocardial ischemia. Polymorphonuclear neutrophil adherence to the coronary vasculature after ischemia was inhibited by S(+)-ketamine, whereas R(-)-ketamine increased coronary vascular fluid leak.     

Caudal analgesia in children: S(+)-ketamine vs S(+)-ketamine plus clonidine

BACKGROUND: The aim of this study was to evaluate postoperative analgesia provided by caudal S(+)-ketamine and S(+)-ketamine plus clonidine without local anesthetic. METHODS: Forty-four children aged 1-5 years consecutively scheduled for inguinal hernia repair, hydrocele repair or orchidopexy were randomly assigned to receive a caudal injection of either S(+)-ketamine 1 mg x kg(-1) (group K) or S(+)-ketamine 0.5 mg x kg(-1) plus clonidine 1 microg x kg(-1) (group KC). Postoperative analgesia and sedation were evaluated by CHEOPS and Ramsay scale from emergence from general anesthesia for 24 h. RESULTS: No statistical difference was observed between study groups with respect to pain and sedation assessment. A slight trend toward a reduced requirement for rescue analgesia in group KC was observed, although not statistically significant. CONCLUSIONS: Caudal S(+)-ketamine 1 mg x kg(-1) and S(+)-ketamine 0.5 mg x kg(-1) plus clonidine 1 microg x kg(-1) are safe and provide effective postoperative analgesia in children without adverse effects.     

右旋氯胺酮在成年人临床麻醉中的应用

背景 右旋氯胺酮在欧美各国已广泛使用,与我国临床使用的消旋氯胺酮比较,其麻醉、镇痛效应更强,精神副反应及分泌物更少,苏醒时间更短.目的 综述右旋氯胺酮的临床应用,为该药在国内麻醉中的应用提供参考.内容 就右旋氯胺酮在麻醉诱导与维持、疼痛治疗、ICU的镇静镇痛及小儿麻醉等方面的临床应用进行归纳总结.趋向 使右旋氯胺酮更加安全、有效、广泛地应用于临床.     

S(+)-ketamine for rectal premedication in children

Our purpose for this prospective, randomized, and double-blinded study was to evaluate the anesthetic efficacy of S(+)-ketamine, an enantiomer of racemic ketamine, compared with a combination of S(+)-ketamine and midazolam, and plain midazolam for rectal premedication in pediatric anesthesia. Sixty-two children, ASA physical status I and II, scheduled for minor surgery, were randomly assigned to be given rectally one of the following: 1.5 mg/kg preservative-free S(+)-ketamine, a combination of 0.75 mg/kg preservative-free S(+)-ketamine and 0.75 mg/kg midazolam, or 0.75 mg/kg midazolam. Preoperative anesthetic efficacy was graded during a period of 20 min by using a five-point scale from 1 = awake to 5 = asleep. Tolerance during anesthesia induction via face mask was graded by using a four-point scale from 1 = very good to 4 = bad. A sufficient anesthetic level (> or = 3) after rectal premedication was reached in 86% in midazolam/S(+)-ketamine premedicated children, in 75% in midazolam premedicated children, but only in 30% in S(+)-ketamine premedicated children (P < 0.05 S(+)-ketamine versus midazolam/S(+)-ketamine and midazolam groups). The incidence of side effects after rectal premedication was rare. Whereas the mask acceptance score was comparable in the three study groups, a 25% rate of complications during anesthesia induction via face was observed in the S(+)-ketamine study group (P < 0.05 versus other study groups). Our conclusions are that S(+)-ketamine for rectal premedication in the dose we chose shows a poor anesthetic effect and a frequent incidence of side effects during induction of anesthesia via face mask compared with the combination of midazolam/S(+)-ketamine and plain midazolam. Dose-response studies of S(+)-ketamine for rectal premedication in pediatric anesthesia may be warranted.     

单纯缺血预处理对兔未成熟心脏不足以提供保护作用

目的探讨单纯缺血预处理(IPC)对兔未成熟心脏缺血再灌注损伤的影响.方法利用Langendorff模型灌注幼兔(14-21d)离体心脏,5min缺血、10min再灌的IPC处理后,观察其在生理体温(39℃)下接受30min缺血、40min复灌的血液动力学、冠脉流出液心肌酶及心肌能量的变化.结果复灌后IPC组与对照组在心率(HR)、冠脉流出量(CF)、左室发展压(LVDP)、左室最大上升和下降速率(±dp/dt)恢复率及室性心律失常发生率无明显差别,肌酸磷酸激酶同工酶(CK-MB)漏出量有增多趋势.而IPC组在全心停灌后心脏缺血跳动时间明显延长(P＜0.01),再灌注末心肌ATP含量显著减少(P＜0.001).结论单纯缺血预处理不能保护未成熟心脏免受心肌缺血再灌注损伤,反而可导致心肌细胞的损伤;其原因可能与全心缺血后,心脏不能很快停跳而导致能量消耗过多有关.     

Enhancement of Na+,K(+)-ATPase and Ca(2+)-ATPase activities in multi-cycle ischemic preconditioning in rabbit hearts.

OBJECTIVE: Ischemic preconditioning (IP) has been shown to attenuate intracellular Na+ accumulation and Ca2+ overload during ischemia and reperfusion, both of which are closely related to the outcome of myocardial damage. We compared the effects of single- and four-cycle IP in Na+,K(+)-activated adenosine 5'-triphosphatase (Na+,K(+)-ATPase) and Ca(2+)-activated adenosine 5'-triphosphatase (Ca(2+)-ATPase) activities in in vivo rabbit hearts, correlating these differences to the quality of protection against subsequent ischemia. METHODS: The morphological outcome was evaluated in in vivo rabbit hearts subjected to 30 min of coronary occlusion and reperfusion for 180 min by assessing the ratio of infarct volume to risk zone volume. The effects of single- and four-cycle preconditioning ischemia were then examined. Another set of in vivo rabbit hearts was subjected to the measurement of ATPase activities at the conclusion of final preconditioning ischemia and at 60 min after reperfusion following 30 min of ischemia. RESULTS: The infarct volume was reduced by single-cycle IP to 38% of that in the control group. The four-cycle IP further reduced the infarct volume, which was 11% of that in the control group. Na+,K(+)-ATPase activity at 60 min after reperfusion in the four-cycle group was increased to 172% of that in the control group (10.8 micromol ADP/h/mg protein), whereas no difference was found in the single-cycle group. On the other hand, Ca(2+)-ATPase activity at the conclusion of IP was increased by single-cycle IP, the value being 255% of that in the control group (4.9 micromol ADP/h/mg protein). The four-cycle IP further increased the activity, and the value was 158% of that in the single-cycle group. CONCLUSIONS: Since increases in Na+,K(+)-ATPase and Ca(2+)-ATPase activities contribute to the decrease in intracellular Ca2+ concentration, the enhancement of these activities by four-cycle IP may be involved in the additional protection.     

S(+)-ketamine for caudal block in paediatric anaesthesia

We have evaluated the intra- and postoperative analgesic efficacy of preservative-free S(+)-ketamine compared with bupivacaine for caudal block in paediatric hernia repair. After induction of general anaesthesia, 49 children undergoing hernia repair were given a caudal injection (0.75 ml kg-1) of S(+)-ketamine 0.5 mg kg-1 (group K1), S(+)- ketamine 1.0 mg kg-1 (group K2) or 0.25% bupivacaine with epinephrine 1:200,000 (group B). No additional analgesic drugs were required during operation in any of the groups. Haemodynamic and respiratory variables remained stable during the observation period. Mean duration of analgesia was significantly longer in groups B and K2 compared with group K1 (300 (SD 96) min and 273 (123) min vs 203 (117) min; P < 0.05). Groups B and K2 required less analgesics in the postoperative period compared with group K1 (30% and 33% vs 72%; P < 0.05). Postoperative sedation scores were comparable between the three groups. We conclude that S(+)-ketamine 1.0 mg kg-1 for caudal block in children produced surgical and postoperative analgesia equivalent to that of bupivacaine.      

Landiolol does not enhance the effect of ischemic preconditioning in isolated rat hearts

Purpose  

To determine the effect of landiolol on ischemic preconditioned rat hearts.     

Racemic, S(+)- and R(-)-ketamine do not increase elevated intracranial pressure

Background: There is controversy regarding the influence of ketamine and its enantiomers on cerebral haemodynamics at increased intracranial pressure (ICP). This study was designed to compare cerebrovascular responses, with particular respect to ICP, to bolus injections of racemic, S(+)- and R(−)-ketamine in an experimental model of intracranial hypertension.
Methods: Nine pigs were anaesthetised with fentanyl and vecuronium during mechanical normoventilation. The ICP was raised with extradural balloon catheters to 23 mmHg. The intra-arterial xenon clearance technique was used to determine cerebral blood flow (CBF). Three 60-s bolus injections of racemic ketamine (10 mg/kg), S-ketamine (5 mg/kg) and R-ketamine (20 mg/kg) were given in a randomised sequence. Cerebral and systemic haemodynamic responses were evaluated before and at 1, 5, 10, 15, 30 and 45 min after each injection.
Results: Racemic ketamine decreased ICP ( P =0.026) by maximally 10.8%, whereas there was no effect on ICP of S- ( P =0.178) or R-ketamine ( P =0.15). All study drugs had similar biphasic effects on CBF, with maximal initial decreases by 25–29%, followed by transient increases by 7–15%, and a reduction of mean arterial pressure by maximally 22–37%.
Conclusions: A decrease or a lack of an increase in ICP in response to intravenous bolus injections of racemic, S- or R-ketamine suggests that the administration of racemic or S-ketamine might be safe in patients with intracranial hypertension due to a space-occupying lesion. The ICP-lowering effect indicates that racemic ketamine might offer a therapeutic advantage over S-ketamine.     

Calcium preconditioning, but not ischemic preconditioning, bypasses the adenosine triphosphate-dependent potassium (KATP) channel.

BACKGROUND: Recent evidence has implicated the KATP channel as an important mediator of ischemic preconditioning (IPC). Indeed, patients taking oral sulfonylurea hypoglycemic agents (i.e., KATP channel inhibitors) for treatment of diabetes mellitus are resistant to the otherwise profoundly protective effects of IPC. Unfortunately, many cardiopulmonary bypass patients, who may benefit from IPC, are chronically exposed to these agents. Calcium preconditioning (CPC) is a potent form of similar myocardial protection which may or may not utilize the KATP channel in its mechanism of protection. The purpose of this study was to determine whether CPC may bypass the KATP channel in its mechanism of action. If so, CPC may offer an alternative to IPC in patients chronically exposed to these agents. METHODS: Isolated rat hearts (n = 6-8/group) were perfused (Langendorff) and received KATP channel inhibition (glibenclamide) or saline vehicle 10 min prior to either a CPC or IPC preconditioning stimulus or neither (ischemia and reperfusion, I/R). Hearts were subjected to global warm I/R (20 min/40 min). Postischemic myocardial functional recovery was determined by measuring developed pressure (DP), coronary flow (CF), and compliance (end diastolic pressure, EDP) with a MacLab pressure digitizer. RESULTS: Both CPC and IPC stimuli protected myocardium against postischemic dysfunction (P < 0.05 vs I/R; ANOVA with Bonferroni/Dunn): DP increased from 52 +/- 4 (I/R) to 79 +/- 2 and 83 +/- 4 mmHg; CF increased from 11 +/- 0.7 to 17 +/- 2 and 16 +/- 1 ml/min; and EDP decreased (compliance improved) from 50 +/- 7 to 27 +/- 5 and 31 +/- 7 mmHg. However, KATP channel inhibition abolished protection in hearts preconditioned with IPC (P < 0.05 vs IPC alone), but not in those preconditioned with CPC (P > 0.05 vs CPC alone). CONCLUSIONS: (1) Both IPC and CPC provide similar myocardial protection; (2) IPC and CPC operate via different mechanisms; i.e., IPC utilizes the KATP channel whereas CPC does not; and (3) CPC may offer a means of bypassing the deleterious effects of KATP channel inhibition in diabetic patients chronically exposed to oral sulfonylurea hypoglycemic agents.     

Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine

BACKGROUND: Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design. METHODS: Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment. RESULTS: Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment. CONCLUSIONS: The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.     

TNF-alpha is required for late ischemic preconditioning but not for remote preconditioning of trauma

BACKGROUND: Ischemic preconditioning (IPC) and remote IPC are cardioprotective phenomena in which ischemia of the myocardium or of a remote tissue, respectively, induces cardioprotection. Despite clinical evidence that surgical trauma can remotely affect myocardial infarction, to date there are no basic science studies addressing the effect of nonischemic trauma at distant sites upon cardiac ischemia/reperfusion (I/R) injury. The objectives of this study were to determine the effects of nonischemic remote surgical trauma upon infarct size after myocardial I/R and to determine the effects of TNF-alpha ablation upon cardioprotective phenomena. MATERIALS AND METHODS: A minimally traumatic mouse model was used to ascertain the effect of remote nonischemic surgical trauma upon I/R injury. TNF-alpha knockout mice were employed to determine the effect of TNF-alpha ablation. RESULTS: Carotid artery vascular surgery remotely exacerbates cardiac I/R injury increasing infarct size by 287% (remote cardiac injury or RCI). Nonischemic, nonvascular trauma (abdominal incision) results in remote preconditioning of trauma (RPCT), decreasing infarct size by 81% (early phase) and 40% (late phase) relative to controls. Finally, TNF-alpha is required for late IPC but is not necessary for RCI or for RPCT. CONCLUSIONS: We show that late IPC is TNF-alpha-dependent and describe two unique TNF-alpha-independent remote effects of nonischemic trauma upon myocardial infarction. Understanding the mechanism of these remote effects will allow the development of novel therapies for the treatment of ischemic heart disease. RPCT and TNF-alpha ablation have an additive protective effect suggesting that combinations of complementary approaches may be a useful strategy for maximizing the clinical efficacy of cardioprotective therapies.     

Infiltrated macrophages contribute to recovery after ischemic injury but not to ischemic preconditioning in kidneys

BACKGROUND: Macrophages are associated with ischemia/reperfusion (I/R) injury; however, the role of macrophages that have infiltrated into tissues remains unclear. Therefore, we investigated whether infiltrated macrophages influence recovery after kidney I/R injury and affect the phenomenon of ischemic preconditioning, in which previous ischemia affords the kidney resistance to subsequent ischemia. METHODS: Mice were subjected to 30 min of bilateral renal ischemia on day 0, then intravenously administered either liposome-encapsulated dichloromethylene bisphosphonate (Cl2MBP; Lipo-clodronate, a remover of tissue macrophages) or PBS (Lipo-PBS) on day 6 and were then subjected to an additional 30 min of bilateral renal ischemia on day 8. RESULTS: Administration of lipoclodronate removed the infiltrated macrophages after I/R. The number of apoptotic and necrotic cells, as well as superoxide and peroxynitrite levels in kidneys from mice that received Lipo-clodronate, was significantly greater than those in kidneys from mice that were administered Lipo-PBS. Proliferating cell nuclear antigen (PCNA) expression was greater in kidneys from mice that were treated with Lipo-clodronate than in those from mice treated with Lipo-PBS. Thirty min of ischemic preconditioning protected the kidneys from 30 min of ischemia induced 8 days later. There was no difference in the plasma creatinine levels of mice treated with Lipo-clodronate or Lipo-PBS. CONCLUSIONS: Our results demonstrated that the infiltrated macrophages removed dead and dying cells and accelerated recovery after ischemia/reperfusion injury but did not make a critical contribution to ischemic preconditioning.     

Analgesic effects of caudal and intramuscular S(+)-ketamine in children

BACKGROUND: Previous studies suggest that caudal administration of ketamine cause effective analgesia. The purpose of the current study was to compare the clinical effectiveness and plasma concentrations of S(+)-ketamine after caudal or intramuscular administration in children to distinguish between local and systemic analgesia. METHODS: After induction of general anesthesia, 42 patients, aged 1 to 7 yr, scheduled to undergo inguinal hernia repair randomly received a caudal (caudal group) or intramuscular (intramuscular group) injection of 1 mg/kg S(+)-ketamine. Intraoperatively, heart rate (HR), mean arterial pressure (MAP) and arterial oxygen saturation were measured. Postoperative measurements included duration of analgesia, a four-point sedation score, and hemodynamic and respiratory monitoring for 6 h in the recovery room. Analgesic requirements in the recovery room were assessed by an independent blinded observer using an observational pain/discomfort scale (OPS). Plasma samples for determination of ketamine concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, and 180 min after injection of S(+)-ketamine. RESULTS: A significantly longer duration of analgesia (P < 0.001) was observed after caudal administration (528 min [220-1,440 min]; median [range]) when compared with intramuscular administration (108 min [62-1,440 min]) of S(+)-ketamine. Plasma levels of ketamine were significantly lower from 10 to 45 min after caudal administration than after intramuscular injection. CONCLUSION: Caudal S(+)-ketamine provides good intra- and postoperative analgesia in children. Despite similar plasma concentrations during most of the postoperative observation period, caudal S(+)-ketamine provided more effective analgesia than did intramuscular S(+)-ketamine, indicating a local analgesic effect.     

S(+)-ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans

PURPOSE: This study investigates the effects of S(+)-ketamine and propofol in comparison to sevoflurane on dynamic cerebrovascular autoregulation in humans. METHODS: Twenty-four patients were randomly assigned to one of the following anesthetic protocols: group I (n=12): 2.5 mg.kg(-1)*hr(-1) S(+)-ketamine, 1.5-2.5 microg*mL(-1) propofol-target plasma concentration; group II (n=12): 2.0 MAC (4.0 %) sevoflurane. Patients were intubated and ventilated with O(2)/air (PaO(2)=0.33). Following 40 min of equilibration dynamic cerebrovascular autoregulation was measured and expressed as the autoregulatory index (ARI), describing the duration of cerebral hemodynamic recovery in relation to changes in mean arterial blood pressure. Statistics: Mann-Whitney U test (statistical significance was assumed when P <0.05). RESULTS: Dynamic cerebrovascular autoregulation was intact in all patients with S(+)-ketamine/propofol anesthesia as indicated by an ARI of 5.4 +/- 1.1. In contrast, dynamic cerebrovascular autoregulation was significantly delayed with 2.0 MAC sevoflurane (ARI=2.6 +/- 0.7) CONCLUSION: Dynamic cerebrovascular autoregulation is maintained with S(+)-ketamine/propofol-based total iv anesthesia. In contrast, 2.0 MAC sevoflurane delayed dynamic cerebrovascular autoregulation. This supports the use of S(+)-ketamine in combination with propofol in neurosurgical patients based on its neuroprotective potential along with maintained cerebrovascular physiology.     

Long-term intrathecal S(+)-ketamine in a patient with cancer-related neuropathic pain

Neuropathic pain sometimes needs invasive pain therapy. We presentthe case of a patient with cancer-related neuropathic pain untreatablewith conventional pain therapy after tumour-embolization. Thepatient was treated successfully with intrathecal (i.t.) administrationof S(+)-ketamine, in addition to morphine. Plasma concentrationsof S(+)-ketamine were measured regularly throughout the treatment.Continuous i.t. administration of S(+)-ketamine over a periodof 3 months demonstrated low plasma levels and no unwanted side-effects.