Non-steady state monitoring by respiratory gas exchange.

Traditionally, the study of CO2 and O2 kinetics in the body has been mostly confined to equilibrium conditions. However, the peri-anesthesia period and the critical care arena often involve conditions of non-steady state. The detection and explanation of CO2 kinetics during non-steady state pathophysiology have required the development of new methodologies, including the CO2 expirogram, average alveolar expired PCO2, and CO2 volume exhaled per breath. Several clinically relevant examples of non-steady state CO2 kinetics perturbations are examined, including abrupt decrease in cardiac output, application of positive end-expiratory pressure during mechanical ventilation, and occurrence of pulmonary embolism. The lesser known area of non-steady state O2 kinetics is introduced, including the measurement of pulmonary O2 uptake per breath. Future directions include the study of the respiratory quotient per breath, where the anaerobic threshold during anesthesia is identified by increasing respiratory quotient.

Postmortem digoxin-like immunoreactive substances (DLIS) in patients not treated with digoxin.

Endogenous digoxin-like immunoreactive substances (DLIS) cross-react in immunoassays of digoxin. The postmortem rise in digoxin levels in patients treated with the drug may be due to its redistribution. It is unclear what is the contribution of DLIS to this increase and whether DLIS are present postmortem in patients not treated with digoxin. The objectives of this study were to determine whether DLIS are present after death in patients not treated with digoxin, whether a postmortem increase in DLIS is detectable and whether sampling site can affect DLIS concentrations. DLIS (measured as digoxin, TDx Abott) were determined in blood samples drawn antemortem from ICU patients; postmortem samples from femoral artery and cardiac chambers were taken at least 12 h after the death of these same patients. DLIS concentrations > or = 0.2 ng/ml were measured in 44 and 40% of patients antemortem and postmortem (femoral), respectively. No difference was found in DLIS levels between antemortem and postmortem femoral and cardiac samples. Age, ICU stay and postmortem sampling time did not affect the postmortem increase in DLIS. None of the levels was in the toxic range. DLIS may be present after death and their concentration does not increase postmortem. The interpretation of postmortem digoxin concentrations that fall in the therapeutic range should be done cautiously; such measurable levels do not necessarily indicate misuse or malicious intent even in patients who had not been treated with the drug.

[Hyperbaric oxygen for carbon monoxide poisoning].

Severe cases of carbon monoxide (CO) poisoning from all over Israel are treated at the Israel Naval Medical Institute with hyperbaric oxygen (HBO). Between 1.11.94 and 15.2.95. 24 cases of CO poisoning were treated. Poisoning was usually due to domestic gas-fired heating systems, CO being the only toxin involved. Since delay between termination of CO exposure and arrival at the emergency department averaged 55 minutes, the level of carboxyhemoglobin measured on presentation did not always reflect the true severity of the poisoning. Poisoning was defined as severe and requiring HBO treatment when 1 or more of the following indications was present: evidence of neurological involvement, cardiographic signs of acute ischemic injury, metabolic acidosis, carboxyhemoglobin level greater than 25%, and pregnancy. 20 (84%) recovered consciousness during the course of 1 session (90 min.) of HBO treatment (pO2 2.8 ATA) or immediately thereafter, with resolution of other signs of CO poisoning. 3 required a second treatment session before their symptoms resolved. A patient who arrived in deep coma with severe cerebral edema died. HBO is an important element in the combined treatment of severe CO poisoning. There should be greater awareness of the danger of CO poisoning and the means of preventing it, both among medical staff and the population as a whole, mainly in areas in which cold weather requires use of heating systems, which may be gas-fired.

Protective effect of stroma-free methemoglobin during cyanide poisoning in dogs.

BACKGROUND: During fire exposure, cyanide toxicity can block aerobic metabolism. Oxygen and sodium thiosulfate are accepted therapy. However, nitrite-induced methemoglobinemia, which avidly binds cyanide, decreases oxygen-carrying capacity that is already reduced by the presence of carboxyhemoglobin (inhalation of carbon monoxide in smoke). This study tested whether exogenous stroma-free methemoglobin (SFmetHb) can prevent depression of hemodynamics and metabolism during canine cyanide poisoning. METHODS: In 10 dogs (weighing 18.8 +/- 3.5 kg) anesthetized with chloralose-urethane and mechanically ventilated with air, baseline hemodynamic and metabolic measurements were made. Then, 137 +/- 31 ml of 12 g% SFmetHb was infused into five dogs (SFmetHb group). Finally, the SFmetHb group and the control group (n = 5, no SFmetHb) received an intravenous potassium cyanide infusion (0.072 mg.kg-1.min-1) for 20 min. Oxygen consumption (VO2) was measured with a Datex Deltatrac (Datex Instruments, Helsinki, Finland) metabolic monitor and cardiac output (QT) was measured by pulmonary artery thermodilution. RESULTS: From baseline to cyanide infusion in the control group, QT decreased significantly (p < 0.05) from 2.9 +/- 0.8 to 1.5 +/- 0.4 l/min, mixed venous PCO2 (PvCO2) tended to decrease from 35 +/- 4 to 23 +/- 2 mmHg, PvO2 increased from 43 +/- 4 to 62 +/- 8 mmHg, VO2 decreased from 93 +/- 8 to 64 +/- 19 ml/min, and lactate increased from 2.3 +/- 0.5 to 7.1 +/- 0.7 mM. In the SFmetHb group, cyanide infusion did not significantly change these variables. From baseline to infused cyanide, the increases in blood cyanide (4.8 +/- 1.0 to 452 +/- 97 microM) and plasma thiocyanate cyanide (18 +/- 5 to 65 +/- 22 microM) in the SFmetHb group were significantly greater than those increases in the control group. SFmetHb itself caused no physiologic changes, except small decreases in heart rate and PvO2. Peak SFmetHb reached 7.7 +/- 1.0% of total hemoglobin. CONCLUSIONS: Prophylactic intravenous SFmetHb preserved cardiovascular and metabolic function in dogs exposed to significant intravenous cyanide. Blood concentrations of cyanide, and its metabolite, thiocyanate, revealed that SFmetHb trapped significant cyanide in blood before tissue penetration.

Measurement of blood CO2 concentration with a conventional PCO2 analyzer.

OBJECTIVES: CO2 content can be determined from the Pco2 in an acidified (forces all CO2 into solution) and diluted blood sample. However, Pco2 concentrations measured in conventional blood gas analyzers are only correct for samples with a significant buffer capacity (such as whole blood), so that mixing with the Pco2 in the rinse solution and tubing walls does not significantly change the sample Pco2. This study describes a calibration method and validation data for the Radiometer Medical ABL2 CO2 electrode system to accurately measure unbuffered blood samples used in the determination of blood CO2 content (or other aqueous fluids). DESIGN: Prospective, criterion standard. SETTING: Laboratory. MEASUREMENTS AND MAIN RESULTS: Blood samples (0.4 mL) were acidified and diluted with 0.2 M lactic acid. After measuring Pco2, CO2 content was calculated using the CO2 solubility coefficient and the dilution factor of 20. CO2 content was determined in a series of sodium carbonate (Na2CO3) solutions spanning the physiologic range of CO2 content. Regression of the measured vs. the actual CO2 content data generated a straight line with a slope of 0.796 and y-intercept of 12.5 (r2 = .99; n = 48). These coefficients were successfully used to correct CO2 content determined in blood samples into which graduated amounts of sodium carbonate were added. CONCLUSIONS: This calibration procedure allows accurate measurement of Pco2 in aqueous samples using the Radiometer ABL2 electrode system, and should be applicable to other blood gas analyzers. Necessary syringes and chemicals are readily available, the method is fast and simple, and the sample volume is small. In the practice of critical care medicine, accurate Pco2 measurement in aqueous acidified and diluted blood provides direct determination of blood CO2 content (useful in calculations of modified Fick cardiac output or tissue CO2 production). Determinations of absolute CO2 content in blood requiring complex methodology are not necessary. In addition, accurate measurement of aqueous gastric Pco2 can help determine gastric pH, which is an important marker of tissue perfusion.

N-acetylcysteine increases the glutathione content and protects rat alveolar type II cells against paraquat-induced cytotoxicity.

A protective effect of N-acetylcysteine in oxidative lung damage was reported by a number of workers; however, the mechanism underlying this effect was not thoroughly elucidated. The present research investigates the protection by N-acetylcysteine against paraquat-induced cytotoxicity to alveolar type II cells, which are known to be specific targets of paraquat toxicity in vivo. We found that addition of 1 mM N-acetylcysteine to alveolar type II cells incubated with 1 mM paraquat reduced the cytotoxic index from 17.4 +/- 1.3% to 9.3 +/- 1.5%. This effect could not be explained by the interference of N-acetylcysteine with the active uptake of paraquat by type II cells. Incubation of these cells with N-acetylcysteine enhances their glutathione content, thus reducing the paraquat- induced depletion of glutathione in these cells. These results suggest that N-acetylcysteine exerts its protective effect by acting as a precursor for glutathione in alveolar type II cells.

Effect of oxygen and sodium thiosulfate during combined carbon monoxide and cyanide poisoning.

In a canine model of combined carbon monoxide (CO) and cyanide (CN) poisoning, cardiac output (QT) and oxygen consumption (Vo2) decreased but recovered to baseline values by 15 min after toxic exposure; elevated blood CN and lactic acidosis persisted for at least another 10 min. Given the rapid spontaneous recovery after cessation of toxic exposure, we questioned the efficacy of usual treatment with oxygen (O2) and sodium thiosulfate (Na2S2O3) for CN poisoning. Accordingly, in seven dogs (26 +/- 3 kg, chloralose and urethane anesthesia), we sequentially administered CO by closed circuit inhalation (231 +/- 42 ml) and potassium CN by intravenous infusion (0.072 mg.kg-1.min-1 for 17 +/- 3 min). Fifteen minutes after toxic exposure, O2 breathing began and Na2S2O3 (150 mg/kg) was infused. Measurements were repeated 10 and 45 min after treatment. At the end of the CN infusion, QT decreased by 43% and Vo2 decreased by 51%, compared to baseline values. Both variables recovered to baseline by 15 min after stopping toxic exposure. Significant lactic (4.8 +/- 2.9 mM) acidosis (7.14 +/- 0.10) persisted for at least another 10 min. Treatment with oxygen and Na2S2O3 did not hasten the recovery of this lactic acidosis or decrease blood cyanide levels compared to nontreated dogs. However, after treatment, plasma thiocyanate significantly increased from 16.3 +/- 12.5 to 94.4 +/- 72.2 microM, as Na2S2O3 participated in the increased metabolism of cyanide to thiocyanate. We conclude that O2 and Na2S2O3 therapy should be continued during combined CO and HCN poisoning. Oxygen increases CO elimination and can enhance anti-CN treatment. After infusion or inhalation of CN, when most CN has already penetrated the intracellular compartment, postexposure sodium thiosulfate increased the metabolism of CN.

Combined carbon monoxide and cyanide poisoning: a place for treatment.

During fires, victims can inhale significant carbon monoxide (CO) and cyanide (CN) gases, which may cause synergistic toxicity in humans. Oxygen therapy is the specific treatment for CO poisoning, but the treatment of CN toxicity is controversial. To examine the indication for treatment of CN toxicity, we have established a canine model to delineate the natural history of combined CO and CN poisoning. In seven dogs (24 +/- 3 kg), CO gas (201 +/- 43 mL) was administered by closed-circuit inhalation. Then, potassium CN was intravenously (i.v.) infused (0.072 mg.kg-1.min-1) for 17.5 +/- 3.0 min. Cardiorespiratory measurements were conducted before and after these toxic challenges. Despite significant CO poisoning (peak carboxyhemoglobin fractions [COHb] = 46% of total hemoglobin [Hb]; elimination t1/2 = 114 +/- 42 min) with attendant decrease in blood O2 content, CO had essentially little effect on any hemodynamic or metabolic variable. On the other hand, CN severely depressed most hemodynamic and metabolic functions. Compared to baseline values, CN caused significant (P < 0.01) decreases in cardiac output (6.4 +/- 2.0 to 3.1 +/- 0.5 L/min) and heart rate (169 +/- 44 to 115 +/- 29 bpm) and decreases in oxygen consumption (VO2) (133 +/- 19 to 69 +/- 21 mL/min) and carbon dioxide production (VCO2) (128 +/- 27 to 103 +/- 22 mL/min). However, these critical hemodynamic and metabolic variables recovered to baseline values by 15 min after stopping the CN infusion, except lactic acidosis which persisted for at least 25 min after the CN infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium-wasting nephropathy in an outbreak of chronic organic mercurial intoxication.

An outbreak of organic mercurial intoxication in a peasant family from the Jordan West Bank is reported. Extrapyramidal symptoms, muscular wasting, oral ulcerations, and renal tubular dysfunction were the main manifestations. Hpyokalemia (1.9-2.7 mEq/l) due to urinary potassium wasting was present in all 4 patients. Type II RTA was observed in 2 cases. Urinary ammonium excretion was increased over the range predicted by the given urinary pH in all the patients. Intrinsic tubular damage, nonreabsorbable anions of catabolic origin, increased prostaglandin synthesis inducing renin-angiotensin axis activation, and, consequently, inappropriate relatively high levels of aldosterone, are advanced as an explanation for potassium wasting.

Evaluation of a liposome system for the delivery of desferrioxamine to lungs in rats.

Liposomes with various lipid composition and sizes, prepared by two different techniques were evaluated for their potential to deliver desferrioxamine to lungs as a treatment against oxidative lung damage. Multilamellar vesicles (MLV) and reverse evaporation vesicles were prepared out of a lipid mixture containing dipalmitoyl phosphatidylcholine, stearyl amine, cholesterol and vitamin E. The administration of desferrioxamine-encapsulated liposomes to rats by the intravenous route at a dose of 100 mg kg-1, significantly prolonged the presence of desferrioxamine in all the tested organs when compared with the administration of free desferrioxamine. The injection of reverse evaporation vesicles extruded through a 2 microns polycarbonate membrane exhibited a longer residence time of the desferrioxamine and of liposomal vitamin E in lungs compared with the other types of liposomes tested. The examination of liposome components in the bronchoalveolar lavage fluid (BALF) and the alveolar macrophages recovered from BALF revealed that about 7 x 10(-3)% of the administered desferrioxamine dose was recovered by this technique at 3 and 17 h after liposome administration. This high residual concentration in the alveolar space confirms the hypothesis that liposomes can be delivered to the lung tissue when encapsulated in alveolar macrophages.

N-acetylcysteine delays the infiltration of inflammatory cells into the lungs of paraquat-intoxicated rats.

We investigated a possible role for N-acetylcysteine (NAC), a well-known antioxidant and free radical scavenger, against oxidative lung damage as observed in the in vivo model of paraquat-intoxicated rats. The administration of two ip doses of 50 mg/kg NAC to paraquat-intoxicated animals did not change the glutathione status of the lungs, as determined by the measurement of nonprotein sulfhydryl (NP-SH) groups. The administration of NAC did however suppress the paraquat-induced release of chemoattractants for neutrophils in the bronchoalveolar fluid when the lavage was carried out 12 hr after the administration of 30 mg/kg paraquat. Also, in the intoxicated NAC-treated animals, the infiltration of inflammatory cells was significantly reduced, as demonstrated by the examination of the cell composition of the bronchoalveolar lavage (BAL), 24 hr after paraquat. Phorbol myristate acetate-stimulated superoxide anion production from the AM isolated from the BAL of paraquat-intoxicated nontreated animals was lower than that of controls, whereas in the NAC-treated animals, it was close to that of the controls. The obtained results indicate that NAC has a protective effect against oxidative lung damage by delaying inflammation. It also prevents the paraquat-induced reduction of superoxide anion production by stimulated AM. In the present model, however, the NAC administration regimen did not affect the survival rate of paraquat-intoxicated rats.

Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure.

Obidoxime is an oxime used in several countries as an antidote in organophosphate intoxication. Its pharmacokinetics were studied in a 20 year-old female with severe and complicated methamidophos intoxication. Obidoxime elimination half life was 6.9 h, volume of distribution 0.845 L/kg, total body clearance 85.4 mL/min, and renal clearance 69 mL/min (creatinine clearance 54 mL/min). Eighty percent of the dose was excreted in the urine over 5 h. Possible reasons for the different pharmacokinetic values as compared with values previously reported in healthy volunteers are discussed. Obidoxime dose should be adjusted according to renal function. More studies are needed to establish the therapeutic window of obidoxime in patients with organophosphate intoxication.

Obidoxime augments the positive inotropic effect of phosphamidon on the isolated working rat heart.

The present study was designed to determine modulation of the direct inotropic effect of an anticholinesterase organophosphorus compound, phosphamidon, by the reactivator obidoxime. We investigated the effects of phosphamidon (n = 9), obidoxime (n = 5), and their combination (n = 5) on the mechanical and energetic indices of left ventricular function, in the isolated working rat heart model. Phosphamidon at a concentration range of 10(-6)-10(-3) M had a positive inotropic effect. Obidoxime at a concentration range of 10(-6)-10(-3) M had no significant effect on heart rate, but did have a statistically significant positive inotropic effect on end-systolic pressure, cardiac output, mean left ventricular pressure, and maximal time derivative of left ventricular pressure (dP/dtmax) (P less than 0.01). Perfusion with 10(-3) M obidoxime caused a 19% increase in left ventricular stroke work and a 31% increase in total pressure-volume area. Perfusion with phosphamidon and obidoxime at concentrations ranging from 10(-6) to 10(-3) M resulted in a more intense inotropic response than the separate drug effects. At the highest combined concentrations tested, cardiac output increased by 60%, left ventricular stroke work increased by 100%, and left ventricular total pressure volume area increased by 111% of their control values (P less than 0.001). We conclude that obidoxime augments the positive inotropic effect of phosphamidon on the isolated working rat heart.

The administration of desferrioxamine to paraquat-intoxicated rats.

We investigated the effect of desferrioxamine, an effective iron chelator, on animal survival and on plasma vitamin E levels after administration of paraquat doses close to the LD50. Male Sprague-Dawley rats received 20 mg paraquat/kg followed by 300 mg desferrioxamine/kg/d given ip over 2 d at 3 equal intervals. The results suggested that desferrioxamine prevented the paraquat-induced depletion of vitamin E, but did not improve the mortality due to paraquat. In ancillary in vitro experiments with a paraquat-based free radical system, where glutathione reductase and NADPH were used as sources of enzymic activity for the redox cycling of paraquat, desferrioxamine effectively prevented the formation of hydroxyl radicals, as determined by deoxyribose degradation.

Effect of phosphamidon and obidoxime on the QT-RR relationship of isolated rat heart.

We studied the effects of phosphamidon (an organophosphate compound), obidoxime (a cholinesterase reactivator), and their combination, phosphamidon/obidoxime (PD/OB) on cardiac cycle length (RR), QT interval, and on QT-RR relationship of isolated rat heart. Cardiac cycle length did not change significantly following perfusion with phosphamidon or obidoxime alone; however, following perfusion with PD/OB, RR significantly increased at high concentrations (10(-3) M) of both drugs. The QT interval lengthened by 5% following perfusion with phosphamidon, did not change following perfusion with obidoxime, and increased by 10% following perfusion with PD/OB. The QT-RR relationship without drugs was positive and linear. Following perfusion with phosphamidon alone, the slope of the relationship decreased significantly, while perfusion with obidoxime alone did not change the QT-RR relationship. Perfusion with PD/OB at low concentrations decreased the slope of the relationship; however, at the highest concentration (10(-3) M) the QT-RR relationship was inverted and became negative. Ventricular arrhythmias as premature ventricular beats, or bigeminies, were noted with increasing frequency following perfusion with increasing doses of phosphamidon. Perfusion with obidoxime did not cause arrhythmias, whereas perfusion with PD/OB caused premature ventricular beats, bigeminies, and ventricular tachycardias at high doses. We suggest that obidoxime modulates the direct effects of phosphamidon on the cardiac repolarization process. PD/OB at high concentrations invert the normal depolarization-repolarization coupling and may therefore potentiate arrhythmias.

Parathion transfer and acetylcholinesterase activity in an in-vitro perfused term human placenta.

Organophosphate transport through the placenta was investigated in an in-vitro placental perfusion system. The system consisted of maternal and fetal reservoirs in which Krebs Ringer bicarbonate buffer with heparin, albumin and glucose was circulated at a constant pH, temperature and pO2. Parathion was analysed by means of gas chromatography with a N-P detector. 14C Antipyrine, a lipid soluble salt, was used as an internal standard, which allowed for the difference in placental size and permeability. A certain amount of parathion passed the placenta and reached the fetal compartment. Glucose consumption was not influenced by the introduction of parathion; neither was the water content of the placental tissue. Acetylcholinesterase activity in placental tissue decreased 50%. The amount of parathion transferred was not negligible and could have caused damage to a fetus.

Direct effects of phosphamidon on isolated working rat heart electrical and mechanical function.

Phosphamidon (2-chloro-3-(diethylamino)-1-methyl-3-oxopropanyldimethyl phosphate) is widely used in agriculture as an organophosphate insecticide. It is a water-soluble cholinesterase inhibitor whose estimated rat LD50 is 9.2 mg/kg, ip. Mechanical and electrophysiologic direct effects of phosphamidon were studied in an isolated working rat heart model. Phosphamidon caused a positive inotropic effect, as indicated by increased maximum time derivative of left ventricular pressure and increased cardiac output. Stroke work and total pressure-volume area increased in a dose-dependent manner following perfusion with phosphamidon. Phosphamidon had in this preparation a biphasic effect on heart rate: at 10(-6) M concentration, heart rate increased, but at higher concentrations (10(-4)-10(-3) M) heart rate decreased significantly. High concentrations of phosphamidon caused a significant prolongation of the Q-T interval. We conclude that phosphamidon has potent cardiotoxic effects, both mechanical and electrophysiologic, on the isolated rat heart.

Exposure to paraquat through skin absorption: clinical and laboratory observations of accidental splashing on healthy skin of agricultural workers.

Data concerning 15 consecutive cases of single exposures of the skin or eyes during work to paraquat solutions are presented. Urine and serum were analysed for paraquat in all these cases at the laboratory of the Israel Poison Information Center. From these data it is apparent that a single exposure of healthy skin to paraquat solutions caused only local lesions. No systemic effect was detected in these patients.

Antidotal therapy of severe acute organophosphate poisoning: a multihospital study.

Out of 859 consecutive cases treated for exposure to organophosphate (PO) insecticides, 53 were included in the study. Criteria for inclusion were severe OP poisoning necessitating artificial ventilation, intensive care monitoring and treatment according to a standard protocol. The protocol was based on relatively high doses of obidoxime, relatively low doses of atropine and overriding with a pacemaker in cases of ventricular arrhythmias and prolonged Q-T interval. Seven patients died during hospitalization. Thirty-two patients (60%) had major central nervous system (CNS) involvement. Five (9.4%) presented severe psychiatric sequelae. Twenty-two patients (41.5%) presented cardiac arrhythmias. Five (9.4%) had liver dysfunction. High frequency of cardiac arrhythmias was observed in patients who received high cumulative doses of atropine and obidoxime; impairment of liver functions was significantly higher in patients who received high cumulative doses of obidoxime. We conclude that each drug should be titrated separately: atropine dosage should be adjusted to the severity of tracheobronchial secretions and bronchospasm, while full doses of obidoxime are justified for the period before "aging" sets in.

Extracorporeal complexation haemodialysis for the treatment of cadmium poisoning. II. In vivo mobilization and removal.

The purpose of this study was to apply our earlier in vitro findings for extracorporeal complexation combined with haemodialysis to in vivo conditions, for the enhancement of cadmium (Cd) removal from dogs. The results showed that ethylenediaminetetraacetic acid (EDTA), glutathione (GSH) and combination of the two agents (EDTA + GSH) facilitated efficient elimination of cadmium. GSH, EDTA and EDTA + GSH treatments brought about the clearance of 2.2, 14.7 and 18.2 micrograms Cd/kg body weight/hr haemodialysis, respectively. Treatment with EDTA + GSH brought about the most rapid extravascular redistribution of the metal.