Olli Kirvelä

Time course of changes in breathing pattern in morphine- and oxycodone-induced respiratory depression

The time course of changes in breathing pattern in opioid‐induced respiratory depression was characterised for two opioids. Intravenous morphine (0.039u2003mg.kg−1 bolusu2003+u20030.215u2003mg.kg−1.h−1 infusion) and oxycodone (0.05u2003mg.kg−1 bolusu2003+u20030.275u2003mg.kg−1.h−1 infusion) were administered to six healthy male volunteers for 2u2003h in a random, double‐blind and cross‐over fashion. Monitoring included pulse oximetry and noninvasive respiratory‐inductive plethysmography for the measurement of breathing pattern. The total amounts of drugs given were 35.1 (0.0)u2003mg [mean (SD)] morphine and 41.3 (8.0)u2003mg oxycodone. Four of the six oxycodone infusions had to be stopped at 99 (14)u2003min because of respiratory depression as judged by pulse oximetry. No morphine infusions were stopped. The first changes in breathing pattern were a decrease in respiratory rate and an increase in the contribution of the rib cage to tidal volume, while the compensatory increase in tidal volume became evident later. A decrease in minute ventilation and inspiratory duty cycle were also found.

The concentration-effect relationship of the respiratory depressant effects of alfentanil and fentanyl

The relative potencies of fentanyl and alfentanil for respiratory depression were determined in eight healthy male volunteers in a double-blinded, randomized study with a cross-over design. The drugs were delivered by computer-driven infusion with logarithmically ascending plasma concentrations until the respiratory rate reached 2/min and/or oxygen saturation decreased below 85% with subjects breathing room air. Ventilation was measured with respiratory inductive plethysmography, indirect calorimetry, and arterial blood gas analysis, and plasma drug concentrations were determined. Pharmacodynamic modeling was performed using a fractional Emax model for minute volume and respiratory rate and the concentrations producing 50% depression (i.e., apparent 50% effective concentration [EC50] values) were determined. Both drugs decreased ventilation in a similar manner, and drug infusions were terminated at mean ± sd measured plasma concentrations of 254 ± 88 ng/mL and 5.1 ± 1.7 ng/mL for alfentanil and fentanyl, respectively. Alfentanil decreased minute volume from baseline by 54% ± 19% and respiratory rate by 40% ± 11% with EC50 values of 234 ± 57 ng/mL and 195 ± 101 ng/mL. The respective decreases for fentanyl were 50% ± 11%, 41% ± 15%, and the estimated EC50 values were 6.1 ± 1.4 ng/mL and 3.5 ± 1.4 ng/mL, respectively. Using the apparent EC50 values, the calculated potency ratio for alfentanil:fentanyl was (mean and 95% confidence interval) 1:39 (1:31–1:46) for minute volume and 1:51 (1:34–1:68) for respiratory rate. This is analogous to the analgesic effect studied earlier. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression.

Comparison of the analgesic effects of intrabursal oxycodone and bupivacaine after acromioplasty

STUDY OBJECTIVESnTo compare the peripheral analgesic effect of oxycodone, an opioid agonist, to the effect of bupivacaine infiltration and parenteral oxycodone administration in conjunction with shoulder surgery.nnnDESIGNnProspective, randomized, double-blind study.nnnSETTINGnUniversity teaching hospital.nnnPATIENTSn42 ASA physical status I and II patients scheduled for shoulder surgery with general anesthesia.nnnINTERVENTIONSnPatients were randomized to three study groups: at the end of the surgery patients received either 10 ml of 0.5% bupivacaine (group BIB) or 5 mg of oxycodone in 10 ml of saline (group OIB) in the subacromial bursa; or 5 mg of oxycodone intramuscularly (group OIM). Postoperative analgesia was provided by patient-controlled analgesia (PCA).nnnMEASUREMENTS AND MAIN RESULTSnThe fentanyl requirements were recorded for the 24-hour postoperative period and the total perioperative period. Postoperative pain was assessed by visual analog scale for pain (VASP). Plasma oxycodone concentrations were measured in groups OIB and OIM. The total perioperative fentanyl consumption was significantly lower in groups BIB (0.97 +/- 0.09 mg) and OIB (1.23 +/- 0.12 mg) than in group OIM (1.61 +/- 0.12 mg) (p = 0.01 and 0.048, respectively). Groups BIB and OIB were similar (p = 0.34). The absorption of oxycodone was significantly lower after subacromial than after intramuscular administration.nnnCONCLUSIONnIntrabursal oxycodone and intrabursal bupivacaine reduced perioperative analgesic requirements similarly. Intrabursal oxycodone may offer an effective, simple, and safe method for postoperative analgesia after shoulder surgery.

Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics

STUDY OBJECTIVEnTo evaluate the effects of high analgesic doses of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamic parameters.nnnSTUDY DESIGNnRandomized, double-blind, cross-over, controlled volunteer study.nnnSETTINGnLaboratory at a university hospital.nnnSUBJECTSn8 healthy male volunteers.nnnINTERVENTIONSnTramadol was given as a 150 mg bolus plus a succeeding 3-hour steady infusion of 250 mg (83.3 mg/hr). Meperidine was given in a similar manner as a bolus dose of 112.5 mg plus 187.5 mg in a 3-hour steady infusion (62.5 mg/hr). Experimental pain was induced using a tourniquet.nnnMEASUREMENTS AND MAIN RESULTSnRespiration was studied noninvasively with respiratory inductive plethysmography and pulse oximetry. Arterial line was used for measurement of hemodynamics and blood sampling. Tramadol did not have any clinically significant effects on respiration, breathing pattern, or hemodynamics, but an increase in plasma epinephrine levels was noted. Meperidine bolus decreased tidal volume (p < 0.05, difference from baseline) and pulse oxygen saturation (from 97% to 94%, p < 0.05), but during the succeeding infusion, the respiratory drive, measured as mean inspiratory flow, was enhanced (p < 0.05 difference from baseline), and the respiratory parameters returned to baseline level. No change in hemodynamics was noted, but a significant increase in plasma norepinephrine and epinephrine levels (from 0.9 to 1.6 nmol/L and from 0.3 to 0.8 nmol/L, respectively; p < 0.05) was observed after meperidine administration. Tramadol caused nausea more often than meperidine (p < 0.05, between treatments).nnnCONCLUSIONSnTramadol exhibited a minimal effect on respiration and breathing pattern in healthy volunteers. The respiratory effects of meperidine bolus were predictable with decreasing tidal volume and pulse oxygen saturation. In contrast, during meperidine infusion, adequate respiration was preserved despite the large amount of meperidine infused.

Treatment of painful neuromas with neurolytic blockade

In 10 patients with intractable pain from neuromas that developed after amputations or other surgery, 20 neuromas were treated with neurolytic blockade. In all cases surgical treatment had been unsuccessful. The blockades were performed with phenol-glycerol. Nine patients became asymptomatic, with no relapse occurring thus far during an observation period of 8-22 months. In 1 patient with 3 neuromas, only one neuroma was completely asymptomatic after a single blockade. This treatment may offer an alternative when surgical treatment has not been successful.

The safety and efficacy of intrabursal oxycodone and bupivacaine in analgesia after shoulder surgery.

Background and Objectives. Peripherally administered opioids, e.g., intra‐articular morphine, exert their analgesic action on local opioid receptors. The present study investigated the safety and efficacy of intrabursal oxycodone and bupivacaine in comparison with bupivacaine infiltration and interscalene brachial plexus block in conjunction with shoulder surgery. Methods. A prospective, randomized study was conducted in 45 patients (15 per group) undergoing elective shoulder surgery during general anesthesia. At the end of the surgery, patients received either 10 mL 0.5% bupivacaine (group B) or 5 mg oxycodone and 10 mL 0.5% bupivacaine (group OB) in the subacromial bursa; interscalene plexus blocks were performed preoperative (group IPB). Postoperative analgesia was provided by patient‐controlled analgesia, and the amount of intravenous fentanyl used during the total perioperative period was recorded. Postoperative pain was assessed by a visual analog scale. Results. The total fentanyl consumption was lower in groups OB and IPB than in group B, and the difference reached statistical significance for both groups (P = .045 and P = .006, respectively). However, the groups OB and IPB did not differ in respect to their fentanyl requirements (P = 1.000). Visual analog scores for pain were lowest in group IBP during the first 6 postoperative hours. The incidence of adverse effects was similar in all groups; serious adverse effects did not occur. Conclusions. According to the present study, intrabursal oxycodone and bupivacaine offer an acceptable and efficient method for postoperative analgesia after shoulder surgery.

The effect of clonidine or midazolam premedication on perioperative responses during ketamine anesthesia

The use of ketamine as a sole anesthetic induces marked central sympathetic stimulation, causing increased heart rate, blood pressure (BP), and oxygen consumption (VO2).Both alpha2-agonists and benzodiazepines have been used to attenuate these potentially harmful ketamine-induced responses. This double-blind, randomized, placebo-controlled study was designed to compare the perioperative metabolic, hemodynamic, and sympathoadrenal responses to IM clonidine (2 [micro sign]g/kg) and midazolam (70 [micro sign]g/kg) premedication during ketamine anesthesia. VO2 was measured continuously using indirect calorimetry in 30 ASA physical status I patients. The patients received ketamine, mivacurium, and fentanyl for the induction of anesthesia. Anesthesia was maintained using a ketamine infusion and fentanyl boluses IV. Preoperatively, both VO2 and BP decreased significantly after the administration clonidine and midazolam compared with placebo (P < 0.01). Intraoperatively, VO2 was higher in the midazolam group than in the placebo and clonidine groups (P < 0.05). Postoperatively, there were no significant differences in BP and VO2, although they stayed at lower level in the clonidine group during the whole postoperative period. Clonidine decreased pre- and postoperative plasma catecholamine concentrations (P < 0.05). Our results indicate that a midazolam-ketamine combination may induce potentially harmful metabolic stimulation, whereas the sympatholytic effects of clonidine on ketamine-anesthetized patients may be beneficial, as perioperative VO2 was decreased. Implications: Ketamine causes sympathetic stimulation with an ensuing increase in oxygen consumption. Anticipating that clonidine might attenuate this response, we measured oxygen consumption in patients undergoing surgery during ketamine anesthesia. Patients treated with a clonidine-ketamine combination had lower intra- and postoperative oxygen consumption than those treated with a midazolam-ketamine combination. (Anesth Analg 1998;87:161-7)

The endoneurial response to neurolytic agents is highly dependent on the mode of application.

BACKGROUND AND OBJECTIVESnThe variability and predictability of neurolytic neural blocks were studied using an experimental rat sciatic nerve model. The goal of the study was to compare endoneurial and clinical responses to commonly used neurolytic agents.nnnMETHODSnThe sciatic nerves of 80 rats were treated either with intra- or perineural injections of 7% phenol-aqua, anhydrous glycerol, or 5% phenol-glycerol. Lidocaine and saline injections were used as controls. Muscle function and trophic changes of the hind limbs were evaluated, and samples for morphologic analysis were taken 1, 2, 4, and 8 weeks after the injections.nnnRESULTSnIntra- and perineural injections of 7% phenol-aqua resulted in gross endoneural damage of the sciatic nerve and hind limb paresis. Perineural 5% phenol-glycerol and anhydrous glycerol injections caused subperineural damage with slight paresis; gross endoneural damage and noticeable paresis were present only after intraneural injections. When 7% phenol-aqua was compared to other neurolytic agents, the differences in the lesion size (P < .0001) were statistically significant after perineural injections. Regeneration occurred in a stereotypic fashion in all neurolytic groups. Axonal sprouts were noted at the injured area 2 weeks after intraneural and 1 week after perineural injections. Motor function had partially recovered at 8 weeks.nnnCONCLUSIONnThere were no differences in the effects of clinically used neurolytic agents after intraneural injections. Although the perineurally applied 7% phenol-aqua induced marked endoneural damage, the destructive effect of glycerol and phenol-glycerol injections seemed to be prevented by the perineurium; phenol-glycerol and glycerol treatments induced subperineural damage only after perineural injections. The ability to penetrate the perineurium favors the use of 7% phenol-aqua in peripheral perineural blocks when complete neurolysis is the goal.

Morphine-induced cardiovascular stimulation : The effects of two doses on healthy subjects

UNLABELLEDnIn humans, morphine induces hypotension, probably because of histamine liberation. Earlier animal studies have, however, suggested that morphine can induce immediate cardiovascular stimulation when given as a sole medication. The aim of this study was to evaluate the initial effects of morphine on circulation, oxygen consumption, and plasma histamine and catecholamine concentrations. Oxycodone was used as a reference drug. Eight healthy volunteers received, in a random, cross-over, double-blinded fashion: 0.07 mg/kg morphine (M1); 0.14 mg/kg morphine (M2); 0.14 mg/kg oxycodone (O); and placebo (P) as a 2-min IV injection for pain. Mean arterial blood pressure (MAP), heart rate (HR), and oxygen consumption (VO(2)) were recorded. Plasma histamine and catecholamine concentrations were determined. Both M1 and M2 elicited an initial, but transient, increase in MAP from 84 +/- 5 to 96 +/- 9 mm Hg (P < 0.05) and from 83 +/- 8 to 100 +/- 10 mm Hg (P < 0.05), respectively. A parallel increase in HR was also seen after M1 (from 62 +/- 12 to 70 +/- 10 bpm, P < 0.05) and M2 (from 67 +/- 9 to 78 +/- 8 bpm, P < 0.05). After M2, this was accompanied by a simultaneous increase in VO(2) from 295 +/- 39 mL/min to 322 +/- 61 mL/min (P < 0.05). After O, as well as P, no increase in MAP or HR was detected. Plasma histamine and catecholamine concentrations were not clearly affected by any of the treatments. We conclude that the immediate effect of morphine on the hemodynamics of healthy volunteers was stimulation, not hypotension. This effect was not seen in conjunction with oxycodone, a morphine-like mu-receptor agonist.nnnIMPLICATIONSnIn this double-blinded, randomized study, we evaluated whether morphine could induce immediate cardiovascular stimulation, as seen previously in animal studies. In healthy volunteers, during a painful stimulus, morphine caused an initial, transient hemodynamic stimulation, accompanied by increased oxygen consumption, without detectable release of histamine or catecholamines into the plasma. Oxycodone caused only minor hemodynamic alterations.

The effect of low‐dose ketamine on fentanyl‐induced respiratory depression

This study evaluated if adding low‐dose ketamine to fentanyl could offer a haemodynamically stable drug combination with little respiratory side‐effects. Eight healthy, consenting male volunteers received in a random, cross‐over and double‐blind fashion both fentanyl 2u2003μgkg−1u2003+u2003ketamine 0.25u2003mgkg−1 and fentanyl 2u2003μgkg−1u2003+ placebo. The fentanyl and placebo reduced minute ventilation, alveolar ventilation and oxygen consumption (u2003pu2003<u20030.05), with little effect on haemodynamics. After fentanyl and ketamine, the decrease in minute ventilation and alveolar ventilation was attenuated compared to the placebo‐containing combination (u2003pu2003<u20030.05), but with a simultaneous increase in oxygen consumption (u2003pu2003<u20030.05) and stimulation of haemodynamics (u2003pu2003<u20030.05). Both treatments decreased oxygen saturation and arterial oxygen pressure similarly. Ketamine thus attenuated the fentanyl‐induced reduction in ventilation without preventing the decrease in blood oxygenation. In conclusion, combining low‐dose ketamine to fentanyl offers no benefits in terms of preventing respiratory depression.