Lawrence Litt

Serious complications related to regional anesthesia: results of a prospective survey in France.

Background Serious complications related to regional anesthesia have previously been described primarily in case reports and retrospective surveys. The authors prospectively evaluated a multicenter series of regional anesthetics, using preplanned criteria to measure the incidence and characteristics of associated serious complications. Methods Requests were sent to 4,927 French anesthesiologists in advance of a subsequent 5-month study period. Participating anesthesiologists were asked for detailed reports of serious complications occurring during or after regional anesthetics performed by them during the study interval. Details regarding each complication then were obtained via a second questionnaire. Results The number of responding anesthesiolgists was 736. The number of regional anesthetics performed was 103,730, corresponding to 40,640 spinal anesthetics, 30,413 epidural anesthetics, 21,278 peripheral nerve blocks, and 11,229 intravenous regional anesthetics. Reports of 98 severe complications were received, with follow-up information being obtained for 97. In 89 cases, complications were attributed fully or partially to regional anesthesia. Thirty-two cardiac arrests, seven of which were fatal, occurred during the study. Of these, 26 occurred during spinal anesthesia, with 6 being fatal, 3 occurred during epidural anesthesia, and 3 more occurred during peripheral blocks. The higher incidence of cardiac arrest during spinal anesthesia (6.4 +/- 1.2 per 10,000 patients) compared with all other regional anesthesia (1.0 +/- 0.4 per 10,000 patients) was statistically significant (P < 0.05). Of 34 neurologic complications (radiculopathy, cauda equina syndrome, paraplegia), 21 were associated either with paresthesia during puncture (n = 19) or with pain during injection (n = 2), suggesting nerve trauma or intraneural injection. Twelve patients who had neurologic complications after spinal anesthetics had no paresthesia during needle placement and no pain on injection. Of these 12 patients (7 with radiculopathy and 5 with cauda equina syndrome), 9 received intrathecal hyperbaric lidocaine, 5%. The incidence of neurologic injury was significantly greater after spinal anesthesia (6 +/- 1 per 10,000 cases; P < 0.05) than after each of the other types of regional procedures (1.6 +/- 0.5 per 10,000 cases for the weighted average). Seizures attributed to elevated serum levels of local anesthetics occurred in 23 patients, but none suffered a cardiac arrest. Conclusions (1) The incidence of cardiac arrest and neurologic injury related to regional anesthesia were very low, but both were more than three SDs greater after spinal anesthesia than after other regional procedures. (2) Two thirds of the patients with neurologic deficits had either a paresthesia during needle placement or pain on injection. (3) Seventy-five percent of the neurologic deficits after nontraumatic spinal anesthesia occurred in patients who had received hyperbaric lidocaine, 5%.

Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain

Clinical studies have shown enhancement of cyclosporine toxicity when co‐administered with the immunosuppressant sirolimus. We evaluated the biochemical mechanisms underlying the sirolimus/cyclosporine interaction on rat brain metabolism using magnetic resonance spectroscopy (MRS) and compared the effects of sirolimus with those of the structurally related RAD. Two‐week‐old rats (25 g) were allocated to the following treatment groups (all n=6): I. control, II. cyclosporine (10 mg kg−1 d−1), III. sirolimus (3 mg kg−1 d−1), IV. RAD (3 mg kg−1 d−1), V. cyclosporine+sirolimus and VI. cyclosporine+RAD. Drugs were administered by oral gavage for 6 days. Twelve hours after the last dose, metabolic changes were assessed in brain tissue extracts using multinuclear MRS. Cyclosporine significantly inhibited mitochondrial glucose metabolism (glutamate: 78±6% of control; GABA: 67±12%; NAD+: 76±3%; P<0.05), but increased lactate production. Sirolimus and RAD inhibited cytosolic glucose metabolism via lactate production (sirolimus: 81±3% of control, RAD: 69±2%; P<0.02). Sirolimus enhanced cyclosporine‐induced inhibition of mitochondrial glucose metabolism (glutamate: 60±4%; GABA: 59±8%; NAD+: 45±5%; P<0.02 versus cyclosporine alone). Lactate production was significantly reduced. In contrast, RAD antagonized the effects of cyclosporine (glutamate, GABA, and NAD+, not significantly different from controls). The results can partially be explained by pharmacokinetic interactions: co‐administration increased the distribution of cyclosporine and sirolimus into brain tissue, while co‐administration with RAD decreased cyclosporine brain tissue concentrations. In addition RAD, but not sirolimus, distributed into brain mitochondria. The combination of cyclosporine/RAD compares favourably to cyclosporine/sirolimus in regards to their effects on brain high‐energy metabolism and tissue distribution in the rat.

Advances in noninvasive cardiovascular imaging: implications for the anesthesiologist.

We have presented a review of recent advances in medical imaging which are relevant to the practice of anesthesia and associated research. The appropriate interpretation and use of the information derived from these noninvasive technologies can prevent unnecessary morbidity and mortality. Echocardiography remains the most advanced tool for noninvasive cardiac imaging because of its applicability for most cardiac disorders and its exquisite spatial resolution. Two-dimensional systems produce real time, dynamic, qualitative assessments of cardiac chamber morphology, size, thickness, and performance. The development of transesophageal echocardiography has brought this imaging power into the operating room for use by anesthesiologists. Recently developed quantitative and color-coded Doppler techniques will reveal intracardiac flow patterns and their alterations by anesthetics and surgery. These advantages are partially offset by inherent difficulties in quantifying echocardiographic data, and the need for highly trained operators for image reproduction. Nuclear cardiology and echocardiology are highly complementary. The scintigraphic methods identify myocardium at risk for infarction, confirm infarction when present, and produce quantitative, highly reproducible estimates of ventricular filling and performance. Time required to obtain data can be very brief for first-pass techniques, and these data are ideally suited for computer processing. Equilibrium studies require a larger dose of radioactive material, but provide excellent assessment of segmental wall motion. Preoperative studies with dipyridamole and Tl can indicate the patients truly at high risk for perioperative myocardial infarction. Monitoring and intensive care efforts may be better allocated with this information. No new technology in the past decade has stirred as much interest among clinicians as magnetic resonance imaging. Like echocardiography, it uses no ionizing radiation and is entirely noninvasive. But, unlike other imaging techniques, it utilizes multiple tissue characteristics to provide quick, highly resolved, tomographic images. Since bone is invisible to the magnetic resonance scanner, tissues inside bony structures are often best revealed with MRI. Nonimaging studies, i.e., spectroscopic data not spatially encoded, may prove to be the most important research currently underway in this field. In vivo estimates of intracellular functions, enzyme kinetics, and drug kinetics and metabolism are already in progress. The effects of anesthetic in the central nervous system and other organs may be explored in ways previously not possible.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral intracellular changes during supercarbia: an in vivo 31P nuclear magnetic resonance study in rats

31P nuclear magnetic resonance (NMR) spectroscopy was used noninvasively to measure in vivo changes in intracellular pH and intracellular phosphate metabolites in the brains of rats during supercarbia (Paco2 ⩾ 400 mm Hg). Five intubated rats were mechanically ventilated with inspired gas mixtures containing 70% CO2 and 30% O2. Supercarbia in the rat was observed to cause a greater reduction in cerebral intracellular pH (pHi) and increase in Pco2 than observed in other experiments with rats after 15 min of global ischemia. Complete neurologic and metabolic recovery was observed in these animals, despite an average decrease in pH; of 0.63 ± 0.02 pH unit during supercarbia episodes that raised Paco2 to 490 ± 80 mm Hg. No change was observed in cerebral intracellular ATP and only a 25% decrease was detected in phosphocreatine. The concentration of free cerebral intracellular ADP, which can be calculated if one assumes that the creatine kinase reaction is in equilibrium, decreased to approximately one-third of its control value. The calculated threefold decrease in the concentration of free ADP and twofold increase in the cytosolic phosphorylation potential suggest that there is increased intracellular oxygenation during supercarbia. Because a more than fourfold increase in intracellular hydrogen ion concentration was tolerated without apparent clinical injury, we conclude that so long as adequate tissue oxygenation and perfusion are maintained, a severe decrease in intracellular pH need not induce or indicate brain injury.

Cerebral uptake and elimination of desflurane, isoflurane, and halothane from rabbit brain: an in vivo NMR study.

The authors used in vivo 19F nuclear magnetic resonance spectroscopy to determine rates of cerebral uptake and elimination of desflurane, isoflurane, and halothane in rabbits. After anesthetizing animals by intramuscular and intravenous injection of methohexital and inhalation of 70% nitrous oxide, intravenous and intraarterial catheters were inserted and a tracheostomy and craniotomy performed. Ventilation was controlled to maintain arterial carbon dioxide tension (PaCO2) from between 35 and 45 mmHg. A 2-2.5-cm diameter circle of dura was exposed, over which a 0.9 x 1.0-cm elliptical surface coil was placed. Cerebral anesthetic concentrations (CC) were estimated from spectra acquired on a 4.7-Tesla spectrometer. Alveolar uptake and elimination also were assessed, using inspired (FI) and end-tidal (denoted FA0 at the end of administration) concentrations measured by gas chromatography. After baseline spectra were obtained, volatile agents were administered for 30 min, followed by a 120-min period of elimination. Our findings demonstrate that cerebral uptake and elimination correlate with solubility: they are most rapid for desflurane, next most rapid for isoflurane, and least rapid for halothane. During administration, cerebral uptake of desflurane (CC/FI = 0.690 +/- 0.049 at 9 min) was approximately 1.7 times faster than isoflurane (CC/FI = 0.691 +/- 0.020 at 15 min) and 3 times faster than halothane (CC/FI = 0.662 +/- 0.040 at 27 min). Similarly, elimination rates for desflurane (CC/FA0 = 0.238 +/- 0.015 at 9 min) were 1.7 times faster than isoflurane (CC/FA0 = 0.236 +/- 0.017 at 15 min) and three times faster than halothane (CC/FA0 = 0.212 +/- 0.033 at 27 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrous oxide and epinephrine-induced arrhythmias.

We asked whether the sympathomimetic effect of nitrous oxide (N2O) predisposed patients receiving N2O to arrhythmias in response to epinephrine administration. We also asked whether aging contributed to the development of arrhythmias, with or without N2O. One hundred patients having transsphenoidal hypophysectomy were randomly assigned to receive anesthesia including (n = 49) or excluding (n = 51) N2O. All patients were given an injection of epinephrine 1:200,000, with 0.5% lidocaine to produce hemostasis. Using intermittent 12-lead and continuous lead II electrocardiography, we determined the incidence of premature ventricular contraction, isorhythmic atrioventricular (AV) dissociation, and changes in T-wave morphology. Patients given N2O had a significantly higher incidence of isorhythmic AV dissociation (61.2% vs 41.2%). A trend toward a higher incidence of multiple premature ventricular contractions (16.3% vs 7.8%) was not statistically significant. Both anesthetic groups had a high incidence of postoperative changes in T-wave morphology (46.9% in the N2O group vs 50.9% in the group not given N2O). Aging alone did not affect the incidence of ventricular ectopic beats, isorhythmic AV dissociation, or changes in electrocardiographic morphology, but correlated with the development of ventricular ectopy during N2O anesthesia. We conclude that the use of N2O correlated with a higher incidence of isorhythmic AV dissociation in response to injection of epinephrine with lidocaine.

Fructose-1,6-Bisphosphate Preserves Adenosine Triphosphate but Not Intracellular pH during Hypoxia in Respiring Neonatal Rat Brain Slices

Background Fructose‐1,6‐bisphosphate (FBP) sometimes provides substantial cerebral protection during hypoxia or ischemia.31 P/sup 1 H nuclear magnetic resonance spectroscopy of cerebrocortical slices was used to study the effects of FBP on hypoxia‐induced metabolic changes. In addition,13 C‐labeled glucose was administered and13 C nuclear magnetic resonance spectroscopy was used to search for FBP‐induced modulations in glycolysis and the pentose‐phosphate pathway. Methods In each experiment, 80 slices (350 micro m) obtained from ten 7‐day‐old Sprague‐Dawley rat litter mates were placed together in a 20‐mm nuclear magnetic resonance tube, perfused, and subjected to 30 min of hypoxia (PO2 < 3 mmHg). Nine experiments were performed, with n = 3 in each of three groups: (1) no treatment with FBP; (2) 60 min of prehypoxia treatment with FBP (2 mM); and (3) 60 min of posthypoxia treatment with FBP (2 mM).31 P/sup 1 H Interleaved nuclear magnetic resonance spectra at 4.7 T provided average adenosine triphosphate, intracellular pH, and lactate. Cresyl violet stains of random slices taken at predetermined time points were studied histologically. Some experiments had [2‐sup 13 C]glucose in the perfusate. Slices from these studies were frozen for perchloric acid extraction of intracellular metabolites and studied with high‐resolution13 C nuclear magnetic resonance spectroscopy at 11.75 T. Results With no pretreatment with FBP, hypoxia caused an [nearly =] 50% loss of adenosine triphosphate, an [nearly =] 700% increase in lactate, and a decrease in intracellular pH to [nearly =] 6.4. Pretreatment with FBP resulted in no detectable loss of adenosine triphosphate, no increase in lactate, and minimal morphologic changes but did not alter decreases in intracellular pH.13 C Nuclear magnetic resonance spectra of extracted metabolites showed that pretreatment caused accumulation of [1‐sup 13 C]fructose‐6‐phosphate, an early pentose‐phosphate pathway metabolite. Posthypoxic treatment with FBP had no effects compared with no treatment. Conclusions During severe hypoxia, pretreatment with FBP completely preserves adenosine triphosphate and almost completely preserves cell morphology but does not alter hypoxia‐induced decreases in intracellular pH. Pretreatment also substantially augments the flux of glucose into the pentose‐phosphate pathway.

Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices

Previous neuron and glial cell culture studies of excessive poly (ADP-ribose) polymerase (PARP-1) activation found NAD+ depletion, glycolytic arrest, and cell death that could be avoided by exogenous tricarboxylic acid cycle (TCA) metabolites, especially pyruvate (pyr). Pyruvate neuroprotection has been attributed to cytosolic NAD+ replenishment, TCA metabolism, and antioxidant activity. We investigated the first two mechanisms in respiring cerebrocortical slices after a 1-h H2O2 exposure to activate PARP-1. H2O2 was followed by a 4-h recovery with oxy-artificial cerebrospinal fluid superfusion having either: (1) no glucose (glc) or pyruvate; (2) 10 mmol/L glc only; (3) 10 mmol/L pyruvate only; (4) both 10 mmol/L glc and 10 mmol/L pyruvate. Poly-ADP-ribosylation was quantified from Western blots and immunohistochemistry. Perchloric acid extracts were quantified with 14.1 T 31P nuclear magnetic resonance spectroscopy. Just after H2O2 exposure, ATP and NAD+ decreased by ≈50%, PCr decreased by 75%, and the ADP/ATP ratio approximately doubled. ATP and NAD+ changes, but not PCr changes, were nearly eliminated if PARP inhibitors accompanied the H2O2. Recovery with both pyruvate and glc was better than with glc alone, having higher ATP (0.161 versus 0.075, P < 0.01) and PCr levels (0.144 versus 0.078, P < 0.01), and higher viable cell counts in TUNEL and Fluoro-Jade B staining. Two-dimensional [1H-13C] HSQC spectra showed metabolism during recovery of 13C glc or pyr. Pyruvate metabolism was primarily via pyruvate dehydrogenase, with some via pyruvate carboxylation. Pyruvate superfusion of PARP-injured brain slices helps replenish NAD+ while providing metabolic fuel. Although this augments recovery, a strong antioxidant role for pyruvate has not been ruled out.

Effects of bicarbonate on arterial and brair intracellular pH in neonatal rabbits recovering from hypoxic lactic acidosis

We used 31P spectroscopy to determine whether administration of a neutralizing dose of bicarbonate in rabbits with lactic acidosis caused a paradoxical brain intracellular acidosis. Ten 10- to 16-day-old rabbits were anesthetized with 0.75% halothane/oxygen and their lungs mechanically ventilated. Metabolic acidosis was induced by decreasing PaO2 to 25 to 35 mm Hg for 1 to 2 hours until the base deficit was 10 to 15 mEq/L. Cerebral ischemia was prevented by maintaining arterial blood pressure at +/- 20% of control value with a venous infusion of epinephrine. Hypoxia was then terminated by administration of 100% oxygen, which was continued for the remainder of the study. After 15 minutes 100% oxygen, 5 mEq/kg 4.2% bicarbonate was administered to five animals; 5 minutes later the same dose was repeated. Control rabbits were given equal volumes of saline solution. In all animals, arterial pH decreased from 7.43 +/- 0.06 to 7.25 +/- 0.08 (SE) during hypoxia, and brain intracellular pH from 7.22 +/- 0.06 to 7.09 +/- 0.09 (SE). Both pH values remained low during reoxygenation. Bicarbonate administration normalized arterial pH (7.41 +/- 0.03), whereas treatment with saline solution did not (7.23 +/- 0.01, P less than 0.05). PaCO2 rapidly increased by 10 mm Hg in the bicarbonate group, and remained elevated; it was unaffected by saline solution administration. Brain intracellular pH in the bicarbonate group increased by 0.12 U over 40 minutes, but intracellular pH in the saline solution group decreased 0.05 pH U (P less than 0.05) over the same period. We conclude that administering a total dose of 10 mEq/kg sodium bicarbonate to neonatal rabbits recovering from hypoxic lactic acidosis increases arterial pH, brain intracellular pH, and PaCO2; it does not produce paradoxical intracellular acidosis in the brain.

Stability of brain intracellular lactate and 31P-metabolite levels at reduced intracellular pH during prolonged hypercapnia in rats.

The tolerance of low intracellular pH (pHi) was examined in vivo in rats by imposing severe, prolonged respiratory acidosis. Rats were intubated and ventilated for 10 min with 20% CO2, for 75 min with 50% CO2, and for 10 min with 20% CO2. The maximum Paco2 was 320 mm Hg. Cerebral intracellular lactate, pHi, and high-energy phosphate metabolites were monitored in vivo with 31P and 1H nuclear magnetic resonance (NMR) spectroscopy, using a 4.7-T horizontal instrument. Within 6 min after the administration of 50% CO2, pHi fell by 0.57 ± 0.03 unit, phosphocreatine decreased by ∼20%, and Pi increased by ∼100%. These values were stable throughout the remainder of the hypercapnic period. Cerebral intracellular lactate, visible with 1H NMR spectroscopy in the hyperoxic state, decreased during hypercapnia, suggesting either a favorable change in oxygen availability (decreased lactate production) or an increase in lactate clearance or both. All hypercapnic animals awakened and behaved normally after CO2 was discontinued. Histological examination of cortical and hippocampal areas, prepared using a hematoxylin and eosin stain, showed no areas of necrosis and no glial infiltrates. However, isolated, scattered, dark-staining, shrunken neurons were detected both in control animals (no exposure to hypercapnia) and in animals that had been hypercapnic. This subtle histological change could represent an artifact resulting from imperfect perfusion-fixation, or it could represent subtle neurologic injury during the hypercapnia protocol. In summary, extreme hypercapnia and low pHi (∼6.5) are well tolerated in rats for periods up to 75 min if adequate oxygenation is maintained. The prolonged stability of metabolite concentrations during hypercapnia makes its use convenient for in vivo animal studies of the relevance of pHi to brain injury.