Walter Klimscha

Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks.

Clonidine in spinal and epidural blocks prolongs anesthesia, but can cause hypotension and bradycardia.The aim of our study was to compare hemodynamic and analgesic effects of spinal versus epidural clonidine alone and after repetitive dosing. In a prospective, randomized, double-blind study, we evaluated 40 patients scheduled for lower extremity orthopedic surgery under continuous spinal or epidural anesthesia with bupivacaine 0.5% (initial dose 5 mg and 50 mg, respectively). In either spinal or epidural technique one-half of patients received clonidine (150 micro gram) in addition to bupivacaine. Repeat doses of the same anesthetic mixture were allowed in cases of subsequent pain. Mean arterial pressure (MAP) and heart rate were recorded for 6 h after each injection. Duration of clinically useful anesthesia was defined as the time from drug administration to first sensation of pain. Intrathecal, but not epidural, clonidine decreased MAP significantly compared with bupivacaine alone. MAP after intrathecal clonidine with bupivacaine was lower than epidural clonidine with bupivacaine 5 and 6 h after injection. Repetitive administration caused no further decrease in MAP. Onset time required to surgical anesthesia (sensory block of T11) did not differ among the four groups. Duration of spinal and epidural anesthesia was increased more than two fold by clonidine. In summary, the addition of clonidine prolongs analgesia by either route. These results may be explained by clonidines sites of action in hemodynamic control and the density of bupivacaine-induced block. (Anesth Analg 1995;80:322-7)

The dose-response of caudal ropivacaine in children.

BACKGROUND Ropivacaine, a new local anesthetic, is less cardiotoxic in adults and is less likely to cause motor blockade than is bupivacaine. The authors evaluated the clinical effectiveness and hemodynamic effects of ropivacaine compared with bupivacaine and the pharmacokinetics of ropivacaine when given for caudal blocks in 56 children 4.1 +/- 1.2 yr old (mean +/- SD). METHODS Patients scheduled for inguinal hernia repair were randomly given a caudal injection (0.75 ml/kg) of ropivacaine, 0.25% (R0.25 group); ropivacaine, 0.5% (R0.5 group); or bupivacaine, 0.25% (B0.25 group). Postoperative measurements included the duration of analgesia, which was our primary outcome variable, and hemodynamic and respiratory monitoring for 4 h in the recovery room. Thereafter, analgesic requirements for the following 24 h were assessed by an independent observer on the ward using an observational pain-discomfort scale, which gives a cumulative score from 5 to 15 to estimate the quality of analgesia by assessment of behavioral objective parameters. Plasma levels of ropivacaine were measured before the procedure was started and 5, 10, 15, 20, 25, 30, and 45 min and 1, 2, 4, 6, 8, and 24 h after caudal block. RESULTS A significantly longer (P < 0.0001) duration of analgesia (median [range]) was observed in the R0.5 group (1,440 [335-1,440] min), whereas the R0.25 group (208 [175-340] min) and the B0.25 group (220 [100-390] min) were comparable. All groups showed a significant decrease in mean arterial blood pressure and heart rate from baseline values, but differences between groups were not observed. CONCLUSION Ropivacaine is well tolerated and provides effective analgesia when given for caudal blockade in small children for inguinal hernia repair.

Analgesic and Hemodynamic Effects of Intrathecal Clonidine as the Sole Analgesic Agent during First Stage of Labor A Dose-Response Study

BACKGROUND Intrathecal clonidine produces dose-dependent postoperative analgesia and enhances labor analgesia from intrathecal sufentanil. The authors evaluated the dose-response potency of intrathecally administered clonidine by itself during first stage of labor with respect to analgesia and maternal and fetal side effects. METHODS Thirty-six parturients requesting labor analgesia were included in this prospective, randomized, double-blind study. Parturients with < 6 cm cervical dilatation received either 50, 100, or 200 microg intrathecal clonidine. The authors recorded visual analog pain score (VAPS), maternal blood pressure and heart rate, ephedrine requirements, and sedation at regular intervals and fetal heart rate tracings continuously. Duration of analgesia was defined as time from intrathecal clonidine administration until request for additional analgesia. RESULTS Clonidine produced a reduction in VAPS with all three doses. The duration of analgesia was significantly longer in patients receiving 200 microg (median, 143; range, 75-210 min) and 100 microg (median, 118; range, 60-180 min) than 50 microg (median, 45; range, 25-150 min), and VAPS was lower in the 200-microg than in the 50-microg group. In the 200-microg group, hypotension required significantly more often treatment with ephedrine than in the other groups. No adverse events or fetal heart rate abnormalities occurred. CONCLUSIONS Fifty to 200 microg intrathecal clonidine produces dose-dependent analgesia during first stage of labor. Although duration and quality of analgesia were more pronounced with 100 and 200 microg than with 50 microg, the high incidence of hypotension requires caution with the use of 200 microg for labor analgesia.

The Efficacy and Safety of a Clonidine/bupivacaine Combination in Caudal Blockade for Pediatric Hernia Repair

We evaluated the analgesic efficacy and hemodynamic and respiratory safety of clonidine when added to bupivacaine for caudal blocks in 58 children aged 38 +/-2 mo (mean +/- SEM). Patients scheduled for ambulatory hernia repair were randomly given a caudal injection (0.75 mL/kg) of either saline placebo (P group), bupivacaine, 0.25% (B group), bupivacaine plus epinephrine 1:200,000 (BE group), bupivacaine plus clonidine 1 micro g/kg (BC1 group), or bupivacaine plus clonidine 2 micro g/kg (BC2 group). Postoperative measurements included duration of analgesia, hemodynamics, and respiratory monitoring for 6 h. Thereafter, parents assessed their childs analgesic requirements at home every 3 h for 18 h. The duration of analgesia (median [range]) was significantly longer (P < 0.05) in the BC1 and BC2 groups (360 [270-360] min and 360 [355-360] min, respectively) compared with the P (77[45-190]), B (346[105-360]), or BE group (300[75-360]). Similarly, the BC1 and BC2 groups required less additional analgesic within the first 24 h. All groups showed a significant decrease in mean arterial pressure compared with baseline values, but the differences among the groups were not significant. Bradycardia and respiratory depression were not observed. Clonidine 1 and 2 micro g/kg can be safely added to bupivacaine caudal blockade in small children for ambulatory hernia repair to achieve an increased duration of analgesia compared with bupivacaine alone or bupivacaine plus epinephrine. Implications: The addition of clonidine, an antihypertensive drug with analgesic properties, to local anesthetics in caudal blocks prolongs postoperative pain relief and reduces the need for additional pain treatment in children after hernia operation.

Continuous Spinal Anesthesia with a Microcatheter and Low-Dose Bupivacaine Decreases the Hemodynamic Effects of Centroneuraxis Blocks in Elderly Patients

This prospective randomized study was designed to investigate the hemodynamic effects and quality of continuous spinal anesthesia (CSA) after rapid injection of a low dose of 0.5% bupivacaine through a 32-gauge microcatheter. The method was compared with continuous epidural (CEA) and single-dose spinal anesthesia (SSA). Seventy-seven elderly patients (ASA II-III) ranging from 57 to 94 yr old and undergoing lower limb surgery were assigned to CSA (n = 26), CEA (n = 26), and SSA groups (n = 25). In all three groups, mean arterial pressure (MAP) and heart rate (HR) were assessed continuously for 30 min after initial injection, as well as after every reinjection of local anesthetic in the CSA and CEA groups. Bupivacaine (0.5%) was used as a local anesthetic. The initial doses were 1 mL of CSA, 10 mL of CEA, and 3 mL of SSA. The reinjection doses were 1 mL of CSA and 5 mL of CEA. In the CSA group, MAP did not decrease, whereas in the CEA group, the maximum decrease was 15% +/- 3% (mean +/- SEM) for the initial injection, 12% +/- 2% for the first repetition, and 13% +/- 2% for the second repetition. In the SSA group, the largest decrease of MAP was 19% +/- 2%. All changes of MAP in the CEA and SSA groups were significantly larger compared with CSA group (P < 0.05). A total of seven patients in these two groups needed vasopressors due to a decrease of MAP of more than 30% from baseline values. Heart rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesic Effects of Caudal and Intramuscular S (+)-Ketamine in Children

BackgroundPrevious 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. MethodsAfter 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. ResultsA 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. ConclusionCaudal 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.

The Effects of Ketamine and Its Enantiomers on the Morphine- or Dexmedetomidine-induced Antinociception after Intrathecal Administration in Rats

Background The spinal administration of some N-methyl-d-aspartate receptor antagonists results in antinociception and potentiates the effects of opioids and &agr;2-adrenoceptor agonists, but ketamine and its enantiomers have not been examined. The present study investigated the interactions of racemic ketamine, R (−)-ketamine and S (+)-ketamine with morphine and with dexmedetomidine. Methods Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose–response and time–course curves were determined for the ketamines (30–300 &mgr;g), morphine (0.1–3.0 &mgr;g), dexmedetomidine (0.3–10.0 &mgr;g), and mixtures of two doses of ketamines (30 or 100 &mgr;g) with different doses of morphine or dexmedetomidine for fixed-dose analysis. Results Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 &mgr;g (95% confidence interval: 1.04–2.32) and 4.85 &mgr;g (3.96–5.79), respectively. A low dose (30 &mgr;g) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 &mgr;g racemic ketamine or S (+)-ketamine, but not R (−)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S (+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S (+)-ketamine also prolonged the effects of dexmedetomidine. Conclusions These data indicate that racemic ketamine and S (+)-ketamine, but not R (−)-ketamine, exhibit similar effectiveness in potentiating the antinociceptive effects of both morphine and dexmedetomidine.

Effects of pentoxifylline on hemodynamics and oxygenation in septic and nonseptic patients

OBJECTIVE To evaluate the effects of pentoxifylline on hemodynamics and systemic oxygenation in septic and nonseptic critically ill patients. DESIGN Prospective clinical investigation. SETTING Intensive care unit (ICU) of a university hospital. PATIENTS Nineteen critically ill patients were included in the study 1 to 4 days after their admission to the ICU. A systemic inflammatory response syndrome was present in 12 patients, fulfilling at least two of the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference criteria. The other seven patients did not fulfill these criteria and were classified as nonseptic. INTERVENTIONS All patients were mechanically ventilated. The dosage of catecholamines was kept constant during the entire study period and at least during 15 mins before the start of the study. In both study groups, pulmonary and radial artery catheters were inserted and 5 mg/kg of pentoxifylline (diluted in 300 mL of physiologic saline) was intravenously administered over a period of 180 mins at a rate of 100 mL/hr. MEASUREMENTS AND MAIN RESULTS Hemodynamic variables, oxygen transport (DO2), oxygen uptake (VO2), and oxygen extraction ratio were determined before pentoxifylline, after 2.5 mg/kg of pentoxifylline, after 5 mg/kg of pentoxifylline, and 60 mins after the termination of pentoxifylline. Repeated-measures analysis of variance and Mann-Whitney test were used for statistical analysis. At baseline, there were significant differences between the septic and the nonseptic groups in mean pulmonary arterial pressure (septic: 31 +/- 5 mm Hg; nonseptic: 26 +/- 7 mm Hg, p < .05), and pulmonary vascular resistance index (PVRI) (septic: 344 +/- 121 dyne.sec/ cm5.m2; nonseptic: 233 +/- 100 dyne.sec/cm5.m2, p < .05). In the septic group, significant increases in heart rate and cardiac index were observed. Systemic vascular resistance index and PVRI decreased. No significant changes in hemodynamic variables occurred in the nonseptic group. In both groups, DO2 and VO2 increased significantly, while oxygen extraction ratio remained unchanged. CONCLUSIONS The administration of pentoxifylline to septic patients results in a significant improvement in hemodynamic performance compared with critically ill nonseptic patients. The better hemodynamic state is accompanied by an increase in DO2 and VO2 with unchanged oxygen extraction ratio.

The synergistic antinociceptive interactions of endomorphin-1 with dexmedetomidine and/or S(+)-ketamine in rats.

Spinal administration of the endogenous &mgr;-opioid agonist peptide, endomorphin-1, results in antinociception in rodents, but there are few data about its interaction with other antinociceptive drugs. We investigated the antinociceptive interactions at the spinal level of endomorphin-1 with the N-methyl-d-aspartate antagonist S(+)-ketamine, the &agr;2-adrenoceptor agonist dexmedetomidine, or both in awake rats. Nociception was assessed by the tail-flick test. Dose-response curves were determined for endomorphin-1 (0.6–50 &mgr;g), for dexmedetomidine (0.1–10 &mgr;g), for mixtures of S(+)-ketamine (30 or 100 &mgr;g) with endomorphin-1 (2–18 &mgr;g) or of endomorphin-1 with dexmedetomidine in a fixed ratio (4:1), and for the triple combination of the three drugs after intrathecal administration. Endomorphin-1 and dexmedetomidine both produced dose-dependent antinociception. The coadministration of 100 &mgr;g S(+)-ketamine significantly enhanced the antinociceptive effect of 6 &mgr;g endomorphin-1. Isobolographic analysis of the combinations of endomorphin-1 and dexmedetomidine revealed a synergistic interaction between these drugs. The 80% effective dose for the triple combination was significantly less than that for either binary combination. These data indicate that S(+)-ketamine and dexmedetomidine, acting via different receptors, produce synergistic antinociceptive interaction with endomorphin-1 at the spinal level. Furthermore, the triple combination of an opioid agonist, an &agr;2-adrenoceptor agonist, and an N-methyl-d-aspartate receptor antagonist shows potent antinociceptive activity.

Antinociceptive effect of the S(+)-enantiomer of ketamine on carrageenan hyperalgesia after intrathecal administration in rats

Ketamine exerts antinociceptive effects in many pain tests.We investigated the antinociceptive effect of intrathecally administered racemic ketamine and its S(+)- and R(-)-enantiomer on carrageenan-induced thermal hyperalgesia with a paw withdrawal test and acute pain (hot plate and tailflick) tests. Rats were prepared with a chronic lumbar intrathecal catheter to receive either saline or ketamine enantiomers in cumulative doses. None of the ketamines (10, 50, or 100 [micro sign]g) had any effect on the withdrawal latency of the contralateral, noninjected paw. In the injected paw, intrathecal saline did not alter carrageenan-induced thermal hyperalgesia, whereas intrathecally applied S(+)-, R(-)-, and racemic ketamine decreased thermal hyperalgesia. However, compared with saline, racemic ketamine had a higher efficacy than S(+)-ketamine, whereas R(-)-ketamine did not achieve statistical significance. Neither S(+)- nor R(-)-ketamine had a significant effect in the tailflick test (10, 100, or 500 [micro sign]g). In the hot plate test, only the largest dose of ketamine (500 [micro sign]g) caused a non-stereospecific, significant increase in hot plate latency; this dose caused supraspinal effects as well. The results demonstrate that the behavioral hyperalgesia associated with carrageenan-induced hindpaw inflammation in rats is attenuated by the intrathecal administration of racemic and S(+)-ketamine, but not R(-)-ketamine, which only displayed an insignificant trend toward a dose-response relationship. This finding warrants further studies to investigate a possible clinical advantage of preservative-free S(+)-ketamine over the currently used preservative containing racemic mixture. Implications: In rats, intrathecal S(+)-ketamine was effective for treating inflammatory pain. Although racemic ketamine has a greater efficacy, S(+)-ketamine is available as a preservative-free drug and might be of clinical interest for future neuraxial administration in different pain states. (Anesth Analg 1998;86:561-5)