Nikolay Ivanovich Pirogov (1810-1881): A pioneering Russian surgeon and medical scientist.

Nikolay Pirogov qualified as a physician from Moscow University in 1828 and then studied surgery and anatomy at University of Dorpat. He developed new surgical techniques, including the eponymous osteoplastic foot amputation. His application of scientifically based techniques extended surgery from a craft to a science. During the Crimean War he initiated the deployment of women as nurses and used triage for dealing with mass casualties. His textbook on field surgery became the standard reference on the subject and his principles remained virtually unchanged until the Second World War. Pirogov died on 5 December 1881 at his estate in Vishnya.

Rhamnose and rhamnitol in dual sugar permeability tests.

Rhamnose is one of the sugars regularly used to conduct the dual sugar permeability test. For more than 30 years, it has been assumed that rhamnose is an inert sugar not metabolized by the human body and only fermented by some colonic bacteria into rhamnulose. While conducting an investigation on gut permeability in children undergoing cardiac surgery, increased concentrations of rhamnitol were found in the urine samples. The present report suggests that rhamnose is not an inert sugar and it is partially metabolized into rhamnitol by the human body.

Morphine-6-glucuronide: morphine's successor for postoperative pain relief?

In searching for an analgesic with fewer side effects than morphine, examination of morphine's active metabolite, morphine-6-glucuronide (M6G), suggests that M6G is possibly such a drug. In contrast to morphine, M6G is not metabolized but excreted via the kidneys and exhibits enterohepatic cycling, as it is a substrate for multidrug resistance transporter proteins in the liver and intestines. M6G exhibits a delay in its analgesic effect (blood-effect site equilibration half-life 4-8 h), which is partly related to slow passage through the blood-brain barrier and distribution within the brain compartment. In humans, M6G's potency is just half of that of morphine. In clinical studies, M6G is well tolerated and produces adequate and long lasting postoperative analgesia. At analgesic doses, M6G causes similar reduction of the ventilatory response to CO2 as an equianalgesic dose of morphine but significantly less depression of the hypoxic ventilatory response. Preliminary data indicate that M6G is associated less than morphine with nausea and vomiting, causing 50% and 75% less nausea in postoperative and experimental settings, respectively. Although the data from the literature are very promising, we believe that more studies are necessary before we may conclude that M6G is superior to morphine for postoperative analgesia.

Gut permeability in neonates after a stage 1 Norwood procedure.

OBJECTIVE: Intestinal mucosal ischemia can occur during and after cardiac surgery. Severe decreases in mucosal perfusion may be a causative factor for postoperative mortality or complications such as necrotizing enterocolitis. Mesenteric perfusion is challenged preoperatively due to an imbalance between the systemic and pulmonary circulations and challenged intraoperatively due to hypothermic circulatory arrest. We have investigated gut permeability in seven patients undergoing stage 1 of the Norwood procedure, applying the dual sugar permeability test with L-rhamnose and lactulose. DESIGN: Seven patients with hypoplastic left heart syndrome: clinical presentation, gut permeability findings, and outcome. SETTING: A 10-bed mixed pediatric intensive care unit in a university hospital. PATIENTS: Seven patients admitted for postoperative care after cardiac surgery. INTERVENTIONS: Determination of gut permeability with the dual sugar permeability test using lactulose and rhamnose. Intestinal permeability was measured after induction of anesthesia and 12 and 24 hrs later. MEASUREMENTS AND MAIN RESULTS: : All patients had abnormal lactulose/rhamnose ratios. One patient, who had a lactulose/rhamnose ratio 12 hrs after surgery of 2.3 (46-times normal), developed necrotizing enterocolitis postoperatively and died 3 days after surgery. CONCLUSIONS: Gut permeability as assessed by the dual sugar permeability test is abnormal in patients with hypoplastic left heart syndrome before and after surgery. Lactulose/rhamnose ratios 46 times the normal value reflect a highly permeable small intestine. This may be a sign of a low output state and may help to identify patients at risk of developing necrotizing enterocolitis.

Effect of dexamethasone on postoperative cardiac troponin T production in pediatric cardiac surgery.

OBJECTIVE: Pediatric cardiac surgery is associated with a temporary rise in cardiac troponin T (cTnT) during the postoperative period. We examined whether dexamethasone given before cardiopulmonary bypass has myocardial protective effects as assessed by the postoperative production of cTnT. DESIGN AND SETTING: Prospective randomized interventional study in the pediatric intensive care unit in a university hospital. INTERVENTIONS: Patients were randomly allocated to act as controls or receive a single dose of dexamethasone (1 mg/kg) during induction of anesthesia. MEASUREMENTS AND RESULTS: cTnT was measured four times postoperatively: immediately after admission to the pediatric intensive care unit (PICU) and 8, 15, and 24 h thereafter. The two groups had similar mean cTnT concentrations on PICU admission: those receiving dexamethasone 1.85 ng/ml (1.55-2.15) and those not receiving it 2 ng/ml (95% confidence interval 1.56-2.51). Concentrations of cTnT 8 h after admission to the PICU differed significantly after 8 h: 1.99 ng/ml (1.53-2.45) in those receiving dexamethasone and 3.08 ng/ml (2.46-3.69) in those not receiving it. After subgroup statistical analysis differences between the two groups remained significant only at 8 h, not those after 15 or 24 h. CONCLUSIONS: The use of dexamethasone (1 mg/kg) before cardiopulmonary bypass is associated with a brief but significant reduction in postoperative cTnT production. The clinical significance of this effect is unclear.

Dexamethasone reduces gut permeability in pediatric cardiac surgery.

OBJECTIVES: Little attention has been paid to the effect of the systemic inflammatory response syndrome on intestinal dysfunction in the postoperative period. Several proinflammatory cytokines have been reported to increase the permeability of intestinal mucosa in vitro. We investigated the effect of dexamethasone on gut permeability in pediatric patients undergoing cardiac surgery by using the dual sugar permeability test and absorption of 2 other saccharides. METHODS: Thirty-four patients scheduled for cardiac surgery with cardiopulmonary bypass were prospectively randomized to either act as control subjects or to receive dexamethasone (1 mg . kg -1) during induction of anesthesia. Intestinal permeability was measured with 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose administered orally after induction of anesthesia and 12 and 24 hours later. RESULTS: Lactulose/rhamnose ratios were increased from the outset in both groups (mean 0.57 [95% confidence interval, 0.24-0.91] for the control group and 0.76 [95% confidence interval, 0.35-1.17] for patients receiving dexamethasone). Although the ratios decreased 12 hours (0.29 [95% confidence interval, 0.17-0.42]) and 24 hours later (0.17 [95% confidence interval, 0.08-0.15]) in the dexamethasone group, in the control group there was a rise at 12 hours (0.77 [95% confidence interval, 0-1.64]), with a slight reduction 24 hours later (0.46 [95% confidence interval, 0.06-0.85]). CONCLUSIONS: Infants and children undergoing cardiac surgery with cardiopulmonary bypass show a significant reduction in gut permeability when dexamethasone is used during induction of anesthesia. Dexamethasone does not affect the intestinal barrier at the functional level, as assessed on the basis of 3-O-methyl-D-glucose and D-xylose absorption.

Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics.

BACKGROUND: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. METHODS: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. RESULTS: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. CONCLUSIONS: Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions.

BACKGROUND: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. METHODS: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18-65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 microg/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood-effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. RESULTS: With blood propofol concentrations increasing from 2 to 7.3 microg/ml, the C(50) of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C(50) of propofol for the return to consciousness decreased from 3.5 microg/ml to 0.6 microg/ml. CONCLUSIONS: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

Isoflurane action in spinal cord indirectly depresses cortical activity associated with electrical stimulation of the reticular formation.

UNLABELLED: Anesthetics act in the spinal cord to ablate both movement and the ascending transmission of nociceptive information. We investigated whether a spinal cord action of isoflurane affected cortical activity as determined by the electroencephalogram desynchronization that occurs after electrical stimulation of the midbrain reticular formation (MRF). Six goats were anesthetized with isoflurane, and neck dissections were performed to permit differential isoflurane delivery to the head and torso. The electroencephalogram was recorded before, during, and after focal electrical stimulation (0.05, 0.1, 0.2, 0.3, and 0.4 mA) in the MRF; in each animal, the brain isoflurane was maintained constant ( approximately 1%). When the torso isoflurane was 0.3% +/- 0.1%, the spectral edge frequency after MRF electrical stimulation (15.3 +/- 1.7 Hz, averaged across all stimulus currents) was more than the spectral edge frequency when the torso isoflurane was 1.2% +/- 0.2% (12.9 +/- 1.0 Hz, averaged across all stimulus currents; P < 0.05). Bispectral index values were similarly affected: 60 +/- 6 when torso isoflurane was low versus 53 +/- 7 at high torso isoflurane (P < 0.05). These results suggest that a spinal depressant action of isoflurane on ascending somatosensory transmission can modulate reticulo-thalamocortical arousal mechanisms, hence possibly reducing anesthetic requirements for unconsciousness and amnesia. IMPLICATIONS: Isoflurane action in the spinal cord indirectly reduces the cortical activity associated with electrical stimulation of the reticular formation, an effect that might contribute to anesthetic-induced amnesia and unconsciousness.

GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner.

UNLABELLED: The enhancing action of propofol on gamma-amino-n-butyric acid subtype A (GABA(A)) receptors purportedly underlies its anesthetic effects. However, a recent study found that a GABA(A) antagonist did not alter the capacity of propofol to depress the righting reflex. We examined whether the noncompetitive GABA(A) antagonist picrotoxin and the competitive GABA(A) antagonist gabazine affected a different anesthetic response, immobility in response to a noxious stimulus (a tail clamp in rats), produced by propofol. This effect was compared with that seen with ketamine and isoflurane. Picrotoxin increased the 50% effective dose (ED(50)) for propofol by approximately 379%; gabazine increased it by 362%, and both antagonists acted in a dose-related manner with no apparent ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED(50) for ketamine by approximately 40%-50%, whereas gabazine increased it by 50%-60%. The isoflurane minimum alveolar anesthetic concentration increased by approximately 60% with the picrotoxin and 70% with the gabazine infusion. The ED(50) for propofol was also antagonized by strychnine, a non-GABAergic glycine receptor antagonist and convulsant, to determine whether excitation of the central nervous system by a non-GABAergic mechanism could account for the increases in propofol ED(50) observed. Because strychnine only increased the immobilizing ED(50) of propofol by approximately 50%, GABA(A) receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABA(A) antagonism can influence the ED(50) for immobility of propofol and the non-GABAergic anesthetic ketamine, although to a different degree, reflecting physiologic antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the neural circuitry underlying immobility) versus physiologic and pharmacologic antagonism for propofol (i.e., a direct effect by antagonism of propofol's mechanism of action). This study also suggests that the immobilizing action of isoflurane probably does not involve the GABA(A) receptor because antagonism of GABA(A) receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol. IMPLICATIONS: IV picrotoxin and gabazine antagonized the immobilizing action of propofol in a dose-related manner, whereas antagonism of the immobilizing action of ketamine and isoflurane was similar, smaller than for propofol, and not dose-related. These results are consistent with a role for gamma-amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.