Jack W. van Kleef

Impact of Anesthesia Management Characteristics on Severe Morbidity and Mortality

Background: Quantitative estimates of how anesthesia management impacts perioperative morbidity and mortality are limited. The authors performed a study to identify risk factors related to anesthesia management for 24-h postoperative severe morbidity and mortality. Methods: A case-control study was performed of all patients undergoing anesthesia (1995-1997). Cases were patients who either remained comatose or died during or within 24 h of undergoing anesthesia. Controls were patients who neither remained comatose nor died during or within 24 hours of undergoing anesthesia. Data were collected by means of a questionnaire, the anesthesia and recovery form. Odds ratios were calculated for risk factors, adjusted for confounders. Results: The cohort comprised 869,483 patients; 807 cases and 883 controls were analyzed. The incidence of 24-h postoperative death was 8.8 (95% confidence interval, 8.2-9.5) per 10,000 anesthetics. The incidence of coma was 0.5 (95% confidence interval, 0.3-0.6). Anesthesia management factors that were statistically significantly associated with a decreased risk were: equipment check with protocol and checklist (odds ratio, 0.64), documentation of the equipment check (odds ratio, 0.61), a directly available anesthesiologist (odds ratio, 0.46), no change of anesthesiologist during anesthesia (odds ratio, 0.44), presence of a full-time working anesthetic nurse (odds ratio, 0.41), two persons present at emergence (odds ratio, 0.69), reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates; odds ratios, 0.10 and 0.29, respectively), and postoperative pain medication as opposed to no pain medication, particularly if administered epidurally or intramuscularly as opposed to intravenously. Conclusions: Mortality after surgery is substantial and an association was established between perioperative coma and death and anesthesia management factors like intraoperative presence of anesthesia personnel, administration of drugs intraoperatively and postoperatively, and characteristics of delivered intraoperative and postoperative anesthetic care.

Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.118A>G ) Does Not Protect Against Opioid-induced Respiratory Depression despite Reduced Analgesic Response

Background:The effect of a single nucleotide polymorphism of the &mgr;-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) was investigated on morphine-6-glucuronide (M6G)–induced analgesia and respiratory depression in a group of healthy volunteers. Methods:Sixteen subjects of either sex received 0.4 mg/kg (n = 8) or 0.6 mg/kg M6G (n = 8). At regular time intervals, the isocapnic acute hypoxic ventilatory response, pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 14 h after drug infusion. Population pharmacokinetic–pharmacodynamic sigmoid Emax models were applied to the respiratory and pain data. All collected data were analyzed using the statistical program NONMEM (San Francisco, CA). Results:Four of the subjects were OPRM1:c.118GA heterozygotes, and the remainder of the subjects were OPRM1:c.118AA homozygotes. M6G analgesia: In contrast to analgesic responses in OPRM1:c.118AA homozygotes, responses were small and inconsistent in OPRM1:c.118GA heterozygotes and best described by the function Effect(t) = baseline (P < 0.01 vs. OPRM1:c.118AA homozygotes). Emax and C50 values in heterozygotes equaled 0.55 ± 0.18 (or a 55% increase in current above baseline) and 161 ± 42 ng/ml, respectively. M6G-induced respiratory depression: For the acute hypoxic response, neither Emax nor C50 (value = 282 ± 72 ng/ml) differed between genotypes. Conclusions:The data indicate that the OPRM1:c.118A>G polymorphism affects opioid analgesic and respiratory effects differentially. Despite reduced analgesic responses to M6G the OPRM1:c.118A>G single-nucleotide polymorphism does not protect against the toxic effects of the tested opioid. However, some caution in the interpretation of the data is needed because of the small sample size. Further studies are needed to explore the link between this polymorphism and respiratory/analgesic responses beyond the small human sample. In OPRM1:c.118AA homozygotes, the potency parameters differed by a factor of 2 for analgesic versus respiratory effect. In this respect, M6G differs favorably from morphine.

Ropivacaine 0.25% versus bupivacaine 0.25% for continuous epidural analgesia in labor: a double-blind comparison.

We compared the effects of continuous epidural infusion of ropivacaine 0.25% with bupivacaine 0.25% on pain relief and motor block during labor, and on the neonate. Seventy-six full-term parturients in active labor requiring epidural analgesia were randomly allocated to receive either bupivacaine 0.25% or ropivacaine 0.25%. Fifteen minutes after a loading dose of 10 mL of the study drug, an epidural infusion with the same drug was started at 6-12 mL/h to maintain an adequate block. Top-up doses of 6-10 mL were given as required. At full cervical dilation, the epidural infusion was discontinued. The onset of pain relief (verbal scale), contraction pain (visual analog scale), intensity of motor block (modified Bromage scale), and duration of motor block were not statistically different between the groups. Apgar scores at 1 and 5 min after delivery were comparable. There was a higher proportion of the neonates in the ropivacaine group (26/31 = 84%) who had a neurologic and adaptive capacity score (NACS) >or=to 35 2 h after delivery than in the bupivacaine group (18/29 = 62%). We conclude that ropivacaine 0.25% and bupivacaine 0.25% are equally effective for epidural pain relief during labor. Ropivacaine may have an advantage over bupivacaine regarding neonatal neurobehavioral performance during the first few hours after delivery, although further studies will be required to substantiate this. (Anesth Analg 1995;80:285-9)

Mechanism of action of an epidural top-up in combined spinal epidural anesthesia.

The purpose of this study was to elucidate the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia. Thirty patients scheduled to undergo lower limb orthopedic surgery were randomly allocated to three groups of 10 patients each. In all patients, a 16-gauge Tuohy needle was introduced into the epidural space. Using the needle through needle technique, each patient received a subarachnoid injection of 10 mg plain bupivacaine 0.5% through a long 27-gauge Whitacre spinal needle introduced into the subarachnoid space through the Tuohy needle. After withdrawal of the spinal needle, an epidural catheter was introduced into the epidural space. After the maximum level of sensory block after the subarachnoid injection had been established, an epidural top-up with 10 mL bupivacaine 0.5% (Group 1) or 10 mL saline (Group 2) was administered; patients in Group 3 received no epidural top-up. The maximum level of sensory block was then assessed for an additional 30 min. After the epidural top-up the maximum level of sensory block increased significantly by 4.8 +/- 1.6 segments in Group 1 and 2.0 +/- 2.0 segments in Group 2. In Group 3 there was a nonsignificant increase of 0.3 +/- 0.5 segments. Intergroup comparisons showed that this increase in Group 1 was significant compared with those in Groups 2 and 3, and that the increase in Group 2 was significant compared with that in Group 3. We conclude that the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia can be explained partly by an epidural volume effect and partly by an effect of the local anesthetic itself. (Anesth Analg 1996;83:382-6)

The Effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine

We studied the influence of age on the neural blockade and hemodynamic changes after the epidural administration of ropivacaine 1.0% in patients undergoing orthopedic, urological, gynecological, or lower abdominal surgery. Fifty-four patients were enrolled in one of three age groups (Group 1: 18–40 yr; Group 2: 41–60 yr; Group 3: ≥61 yr). After a test dose of 3 mL of prilocaine 1.0% with epinephrine 5 &mgr;g/mL, 15 mL of ropivacaine 1.0% was administered epidurally. The level of analgesia and degree of motor blockade were assessed, and hemodynamic variables were recorded at standardized intervals. The upper level of analgesia differed among all groups (medians: Group 1: T8; Group 2: T6; Group 3: T4). Motor blockade was more intense in the oldest compared with the youngest age group. The incidence of bradycardia and hypotension and the maximal decrease in mean arterial blood pressure during the first hour after the epidural injection (median of Group 1: 11 mm Hg; Group 2: 16 mm Hg; Group 3: 29 mm Hg) were more frequent in the oldest age group. We conclude that age influences the clinical profile of ropivacaine 1.0%. The hemodynamic effects in older patients may be caused by the high thoracic spread of analgesia, although a diminished hemodynamic homeostasis may contribute.

Effects of Subanesthetic Halothane on the Ventilatory Responses to Hypercapnia and Acute Hypoxia in Healthy Volunteers

Background: The peripheral chemoreceptors are responsible for the ventilatory response to hypoxia (acute hypoxic response) and for 30% of the normoxic hypercapnic ventilatory response. To quantify the effects of subanesthetic concentrations of halothane on the respiratory control system, in particular on the peripheral chemoreceptors, we studied the response of humans to carbon dioxide and oxygen at two subanesthetic concentrations of halothane. Methods: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.3 mmHg) and step decreases in end-tidal oxygen tension (arterial hemoglobin oxygen saturation 82 ± 2%; duration of hypoxia 5 min) were performed in nine healthy male subjects during 0, 0.05 (HA-1), and 0.1 minimum alveolar concentration (HA-2) halothane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set. Results: Fifty-six carbon dioxide responses and 27 oxygen responses were obtained. The peripheral carbon dioxide sensitivities averaged to 0.76 ± 0.141·min-1· mmHg-1(control), 0.50 ± 0.12 1·min-1 · mmHg-1 (HA-1), and 0.30 ± 0.08 1·min-1·mmHg-1(HA-2; P < 0.01 vs. control). The central carbon dioxide sensitivity did not differ significantly among treatment groups (control, 1.47 ± 0.22 1· min-1· mmHg-1; HA-1, 1.41 ± 0.51 1·min-1 mmHg-1; and HA-2, 1.23 ± 0.30 1·min-1·mmHg-1). The time constants of the central chemoreflex loop showed a large decrease during the administration of 0.1 minimum alveolar concentration halothane. The acute hypoxic response declined from 15.0 ± 3.9 1·min-1 to 10.9 ± 2.9 1·min-1 (HA-1) and 4.8 ± 1.4 1·min-1 (HA-2; P < 0.01 vs. control and HA-1). All values are means ± SEM. Conclusions: The results show depression of the ventilatory responses to hypoxia and hypercapnia during inhalation of subanesthetic concentrations of halothane. The depression is attributed to a selective effect of halothane on the peripheral chemoreflex loop. The oxygen and carbon dioxide responses mediated by the peripheral chemoreceptors are affected proportionally. It is argued that the decrease in central time constants is caused by an effect of halothane on central neuronal dynamics.

Epidural anesthesia with lidocaine and bupivacaine: effects of epinephrine on the plasma concentration profiles.

The effects of epinephrine on the plasma concentrations and derived pharmacokinetic parameters were studied after epiditral administration of lidocaine and bupivacaine. Addition of epinephrine to the local anesthetic solutions reduced the mean peak plasma concentrations of lidocaine and bupivacaine from 2.2 to 1.7 μg/ml (23%) and from 0.73 to 0.53 μg/ml (28%), respectively, but did not alter the times at which the peak concentrations were reached. Epinephrine also did not alter the terminal half-lives or the total plasma clearances. The results suggest that addition of epinephrine to minimize plasma concentrations is as relevant with bupivacaine as it is with lidocaine.

Acute Pain and Central Nervous System Arousal Do Not Restore Impaired Hypoxic Ventilatory Response during Sevoflurane Sedation

Background To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation. Methods Step decreases in end‐tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1‐Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end‐tidal partial pressure of carbon dioxide was held constant at a value slightly greater than baseline (44 mmHg). To assess the central nervous system arousal state, the bispectral index of the electroencephalogram was monitored. Values are mean+/‐SE. Results Pain caused an increase in prehypoxic baseline ventilation before and during sevoflurane inhalation: C = 13.7+/‐0.9 l *symbol* min‐1, C + P = 16.0+/‐1.0 l *symbol* min‐1 (P < 0.05 vs. C and S), S = 12.7+/‐1.2 l *symbol* min‐1, and S + P = 15.9+/‐1.1 l *symbol* min‐1 (P < 0.05 vs. C and S). Sevoflurane decreased the acute hypoxic ventilatory response in the absence and presence of noxious stimulation: C = 0.69+/‐0.20 l *symbol* min‐1 (% change in arterial hemoglobin‐oxygen saturation derived from pulse oximetry [SP O2])‐1, C + P = 0.64 +/‐0.13 l *symbol* min‐1 *symbol* %SP O2‐1, S = 0.48+/‐0.15 l *symbol* min‐1 *symbol* %SP O2‐1 (P < 0.05 vs. C and C + P) and S + P = 0.46+/‐0.12 l *symbol* min‐1 *symbol* %SP O2‐1 (P < 0.05 vs. C and C + P). The bispectral indexes were C = 96.2+/‐0.7, C + P = 97.1 +/‐0.4, S = 86.3+/‐1.3 (P < 0.05), and S + P = 95.0 +/‐1.0. Conclusions The observation that acute pain caused an increase in baseline ventilation with no effect on the acute hypoxic ventilatory response indicates that acute pain interacted with ventilatory control without modifying the effect of low‐dose sevoflurane on the peripheral chemoreflex loop. Acute pain increased the level of arousal significantly during sevoflurane inhalation but did not restore the approximately 30% depression of the acute hypoxic ventilatory response by sevoflurane. The central nervous system arousal state per se did not contribute to the impairment of the acute hypoxic ventilatory response by sevoflurane.

Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery: pharmacokinetic evaluation.

Background Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative phase. Therefore, the authors evaluated the pharmacokinetics of ropivacaine, administered by 72-h epidural infusion to provide postoperative analgesia. Methods Twenty-eight patients, scheduled for major orthopedic surgery during combined epidural and general anesthesia received a bolus dose of ropivacaine (50 or 75 mg), followed by constant-rate (10 ml/h) epidural infusion of ropivacaine 2 mg/ml (group 1) or 3 mg/ml (group 2). Total and unbound plasma concentrations of ropivacaine and pipecoloxylidide and plasma concentrations of &agr;1-acid glycoprotein were determined. In addition, the urinary excretion of ropivacaine and major metabolites was measured. Results Total plasma concentrations of ropivacaine increased steadily during the infusion, reaching 2.7 ± 0.7 and 2.9 ± 0.5 mg/l in groups 1 and 2 after 72 h constant-rate infusion. Unbound ropivacaine concentrations reached average steady state levels of approximately 0.06 and 0.07 mg/l. Total and unbound concentrations of pipecoloxylidide increased to 1.0 ± 0.4 and 0.4 ± 0.2 mg/l (group 1) and 1.2 ± 0.4 and 0.5 ± 0.1 mg/l (group 2) after 72 h infusion. &agr;1-Acid glycoprotein concentrations initially decreased, but thereafter increased steadily to approximately twice the baseline values. Conclusions Postoperative increases in plasma &agr;1-acid glycoprotein concentrations enhance the protein binding of ropivacaine and pipecoloxylidide, causing divergence of total and unbound plasma concentrations.

Does Subanesthetic Isqflurane Affect the Ventilatory Response to Acute Isocapnic Hypoxia in Healthy Volunteers

BackgroundDifferences in results studying the effects of subanesthetic concentrations of volatile agents on the hypoxic ventilatory response may be related to the conditions under which the subjects were tested. In this study we investigated the effects of 0.1 minimum alveolar concentration (MAC) of isoflurane on the hypoxic ventilatory response without and with audiovisual stimulation. MethodsStep decreases in arterial hemoglobin oxygen saturation from normoxia into hypoxia (arterial hemoglobin oxygen saturation 80% ± 2% duration of hypoxia 5 min) were performed in ten healthy subjects. We obtained four responses per subject: one without isoflurane in a darkened, quiet room; one without isoflurane with audiovisual input (music videos); one in a darkened room at 0.1 MAC isoflurane; and one at 0.1 MAC isoflurane with audiovisual input (subjects were addressed to keep their eyes open). Experiments were performed against a background of isocapnia (end-tidal carbon dioxide tension 1–1.4 mmHg above initial resting values). ResultsThe hypoxic responses averaged 0.54 ± 0.09 1 * min-1 * %-1 (without isoflurane in a darkened, quiet room), 0.27 ± 0.06 1 * min-1 * %-1 (in a darkened room at 0.1 MAC isoflurane; P< 0.01), 0.56 ± 0.131 * min-1 * %-1 (without isoflurane with audiovisual input), and 0.47 ± 0.13 1 * min-1* %-1 (at 0.1 MAC isoflurane with audiovisual input). Values are means ± SE. During 0.1 MAC isoflurane administration, all subjects showed a depressed hypoxic response when not stimulated, while with stimulation two subjects had an increased response, four a decreased response and four an unchanged response compared to control. ConclusionsWe observed an important effect of the study conditions on the effects that 0.1 MAC isoflurane has on the hypoxic ventilatory response. A depressant effect of subanesthetic isoflurane was found only when external stimuli to the subjects were absent. With extraneous audiovisual stimuli the effect of isoflurane on the response to hypoxia was more variable. On the average, however, the response then was not depressed by isoflurane.