Victims of domestic or industrial fires may inhale smoke containing toxic amounts of carbon monoxide (CO) and hydrogen cyanide (CN) gases [1-3]. CO gas is a well recognized combustion product. More recently, hydrogen CN has been recognized as an important toxic gas produced in fires by the thermal decomposition of nitrogenous materials, including natural fibers (wool and silk) and synthetic polymers (polyurethane and polyacrylonitrile) [1,3,4].
CO converts oxyhemoglobin to carboxyhemoglobin (COHb)  and shifts the oxyhemoglobin (oxyHb) dissociation curve to the left , which decreases the O2 delivery capacity to the tissues. CN binds to cytochrome oxidase, the last cytochrome in oxidative phosphorylation, to block cellular aerobic metabolism [4-6] and decrease the tissue utilization of O2. Recent studies have suggested a synergistic effect of CO and CN on oxygen metabolism in the body, such that lower concentrations of each gas are more toxic when they are present together [2-4,7,8].
CO poisoning is rapidly detected by the measurement of increased blood COHb concentration, and standard treatment is normobaric or hyperbaric O2. However, the detection of CN poisoning in blood is difficult. The measurement of CN concentration in blood is neither universally available nor immediate . Hence, the diagnosis of CN poisoning, by eventual clinical suspicion [1,9], is often delayed. However, CN has a short half-life in blood [1,3]. Because specific antidotes generally remain in the extracellular space , their administration may be late and ineffective. Conceivably, the cessation of exposure to CN may be the first important treatment for the victim. Furthermore, currently accepted antidotes for CN poisoning may be ineffective or even dangerous. Sodium thiosulfate (S2 O3 Na2) is usually administered to increase the enzymatic conversion of CN to plasma thiocyanate . However, experimental studies have often tested the effectiveness of S2 O3 Na2 as a protective agent administered before exposure [6,10]. For a fire victim, S2 O3 Na2 would be administered as treatment only after exposure to CN. Another component of treatment for CN poisoning is the administration of sodium nitrite to induce methemoglobinemia. Methemoglobin (metHb) avidly binds CN but further decreases oxygen-carrying capacity [6,11,12] that is already reduced by the presence of COHb.
Therefore, we believe that the natural course of combined CO and CN poisoning must be examined first to delineate the effects of stopping toxic exposure before the testing of any specific antidote. Accordingly, to simulate the poisoning of a victim rescued from a fire, we have developed a canine model of CO and CN poisoning. Before and after the induction of CO and then CN poisoning, we conducted serial measurements to ascertain the temporal changes in cardiovascular, gas exchange, and metabolic variables and the pharmacokinetics of CO and CN. We mechanically ventilated the dogs throughout the study to exclude superimposed hypoxia that could occur from respiratory depression induced by CN .
This study was approved by the University of Chicago Animal Care Committee in accordance with guidelines of the American Physiological Society. Seven mongrel dogs (24 +/- 3 kg) were anesthetized with intravenous (IV) chloralose (160 mg/kg) and urethane (800 mg/kg) and ventilated with air through an orotracheal tube. Tidal volume (VT, 21.5 +/- 3.4 mL/kg) and respiratory frequency (f, 12.5 +/- 0.8 breaths/min) were adjusted to maintain Pa CO2 near 36 mm Hg. At the proximal end of the orotracheal tube, we monitored airway opening pressure. Exhaled gas passed through a pneumotachometer (Fleisch No. 2; Menatoba Co., Menatoba, Switzerland) attached to a differential pressure transducer (model DP45; Validyne, Northridge, CA) and carrier demodulator (model CD19). This analog-exhaled flow signal was digitized at 100 Hz and stored in a microcomputer. A large bore three-way stopcock allowed intermittent collections of mixed expired gas.
We inserted a femoral artery catheter to monitor systemic pressure (Psa) and to sample arterial blood and a venous catheter to administer drugs and fluids. Through the other femoral vein, we advanced a balloon-tipped catheter into a pulmonary artery branch for pressure monitoring (Ppa), intermittent determinations of pulmonary wedge pressure (Ppw), mixed venous blood sampling, and thermodilution measurements of cardiac output (QT; Model 9510A computer, Edwards, Irvine, CA). We monitored the electrocardiogram (lead II). Vascular pressures were measured with model P23 transducers (Gould, Oxnard, CA). All signals were amplified and displayed on a polygraph. The animals were then positioned prone for the remainder of the experiment.
To cannulate the sagittal sinus [5,13], the head of each animal was supported by two clamps positioned in the external auditory canals. Through a midline sagittal incision, the scalp was dissected and retracted laterally. We used a trephine to make a burr hole cephalad to the occipital prominence. The burr hole was enlarged as necessary with the trephine or rongure. After achieving hemostasis with bone wax and Surgicel (Johnson & Johnson Medical, New Brunswick, NJ), a curved 20-gauge IV catheter was introduced over a needle in a caudal direction into the sagittal sinus. After confirming free aspiration of blood, the catheter was fixed to bone with dental acrylic cement.
Before the protocol began, each animal was paralyzed with pancuronium (0.2 mg/kg). Sodium bicarbonate (NaHCO3) was administered to maintain a physiologic arterial pH. Normal saline was administered to achieve a Ppw near 8 mm Hg. During the experimental protocol, saline was infused at a constant rate. Hourly doses of chloralose (20 mg/kg), urethane (100 mg/kg), and pancuronium (0.08 mg/kg) were administered to maintain anesthesia and paralysis.
The experimental protocol began with baseline (BsLn) measurements, consisting of simultaneous arterial, mixed venous, and sagittal sinus blood samples, digital collection of exhaled flow with a simultaneous expired gas collection, vascular pressures, and cardiac output (QT). Then the measurement sequence was repeated after the inhalation of CO and at the end of the potassium cyanide (KCN) infusion. Three further measurement stages were conducted after 15, 25, and 75 min (Post15, Post25, and Post75, respectively). Then, after ensuring adequate anesthesia, the animal was administered a lethal dose of IV KCl.
The dose of CO (mL) was calculated by BW centered dot VBL centered dot Hb centered dot 1.34 centered dot FCOHb, where BW was body weight (kg), VBL was the blood volume (0.75 dL/kg), Hb was the hemoglobin concentration (g/dL), 1.34 was the Hb CO binding capacity (mL CO/g Hb), and FCOHb was the desired COHb fraction. In preliminary experiments, we found that desired FCOHb needed to be set near 0.7 to achieve significant COHb levels, because a significant amount of CO quickly distributed to tissues (see below). The CO was injected into the inspiratory limb of a closed circuit that incorporated a ventilator and CO2 absorber. Through a low flow rotameter, oxygen was added to maintain the O2 concentration between 17% and 23%. Complete uptake of CO from the circuit was monitored by mass spectrometer (model 6000, Ohmeda, Madison, WI), which qualitatively detected CO as spillover into the nitrogen channel (same molecular weight) and the CO2 channel (conversion to C12 fragment) (personal communication, W. Thiessen, Project Engineer, Ohmeda Corporation). After injecting the CO into the circuit, serial blood samples were obtained for determination of COHb. For investigator protection, absence of CO leakage from the circuit was confirmed with a sensitive CO detector.
KCN was prepared each experimental day. Two drops of 0.1 N sodium hydroxide (NaOH) were added to alkalinize 10 mL of 0.9% sodium chloride (NaCl) before adding KCN powder. For each dog, we prepared a KCN solution that delivered 0.072 mg centered dot kg-1 centered dot min-1 when infused at 1 mL/min into the right heart through a separate lumen of the pulmonary artery catheter. We infused the CN solution for 17.5 +/- 3.0 min, a duration which, in preliminary experiments, resulted in significant but nonlethal decreases in QT and O2 consumption (VO2).
The pH, PCO2, and PO2 of blood samples were measured at 37 degrees C and corrected to body temperature . Fractions of oxyHb, COHb and metHb and total hemoglobin (Hb) concentration were measured with a cooximeter (model IL 482; Instrumentation Laboratory, Lexington, MA) calibrated for dog blood. Oxygen contents were then determined by (Hb centered dot %oxyHb centered dot 1.34) + (0.003 centered dot PO2), where 1.34 is the Hb O2 binding capacity (mL O2/g Hb) and 0.003 is the solubility of O2 (mL O2 centered dot dL blood-1 centered dot mm Hg-1). Blood lactate concentrations were measured with a lactate analyzer (model 23L; Yellow Springs Instrument, Yellow Springs, OH).
Blood CN concentration was measured electrochemically by silver rotating disk electrode and dropping mercury electrode . Thiocyanate was oxidized to CN with permanganate prior to the determination of plasma thiocyanate concentration.
VO2 was calculated by VE centered dot (FI O2 centered dot FE N2/FI N2)--FE O2, where FI O2 and FI N2 were the inspired fractions of O2 and N2 and FE O (2) and FE N2 were the respective mixed expired fractions in a collection of exhaled gas. A computer algorithm determined minute ventilation (VE) by integrating the digital exhaled flow data with respect to time. Carbon dioxide production (VCO (2)) was calculated by VE centered dot FE CO2, where FE CO (2) was the mixed expired CO2 fraction. Gas fractions were measured by the mass spectrometer, calibrated with standardized gas mixtures provided by the manufacturer. Following standard practice, gas volumes were corrected to standard temperature and pressure dry, except minute ventilation which was expressed as body temperature saturated. We fit pharmacokinetic CO and CN data to exponential equations by least-squares regression and report the time to reach one-half of the final value of the function (t1/2) and the coefficient of determination (r2). Pulmonary vascular resistance was calculated by (Ppa--Ppw) centered dot QT-1 centered dot 80; QT was cardiac output, and 80 was a units conversion factor.
We used repeated-measures analysis of variance to test each variable for differences among stages . If a significant F statistic resulted (P < 0.05), then the differing stages were identified by the Student-Newman-Keuls multiple comparison test. The paired t-test was used for selected comparisons. Data are reported as mean +/- SD.
(Figure 1) depicts the change in COHb percentage for the seven dogs. After injection of the CO gas (201 +/- 43 mL standard temperature and pressure dry) into the closed ventilating circuit, COHb at BsLn (1.1% +/- 0.2%) increased quickly to a peak value of 45.9% +/- 6.4%. By least-squares regression of data from each dog to a single exponential function, we calculated an average t1/2 of 50 +/- 13 s (average r2 = 0.982). Assuming a one-to-one molar binding of CO to Hb, 66% +/- 11% of the administered CO gas was present as peak COHb. Then, the decrease in COHb followed a single exponential decay with an average t1/2 of 114 +/- 42 min (average r2 = 0.928).
During the KCN infusion, average CN concentration in whole blood (n = 6) steadily increased from 52.0 +/- 28.1 to 164.2 +/- 27.1 micro Meter Figure 2. By the end of the CN infusion, metHb concentration significantly decreased to 0.33% +/- 0.11%, compared to a BsLn value of 0.66% +/- 0.21%. After stopping the CN infusion, the regression of mean [CN] data to a single exponential function resulted in t1/2 of 62.3 min and r2 of 0.756. Inspection of the plot of natural logarithmic [CN] versus time suggested that the alpha distribution phase did not end until 20 min after stopping the CN infusion. When the 20- to 70-min values were analyzed separately, the elimination phase t1/2 was 129 min and r2 was 0.999. By 70 min after stopping the CN infusion, CN concentration was not different than BsLn. During and after the CN infusion, plasma thiocyanate concentration (n = 6) steadily increased from 7.0 +/- 4.4 to 40.2 +/- 14.5 micro Meter (p < 0.01).
CO had no significant effect on any hemodynamic variable. During CN infusion, QT significantly decreased to 3.1 +/- 0.5 L/min, from a BsLn value of 6.4 L/min Figure 3, and then completely recovered by 15 min after stopping the CN infusion. These changes in QT were paralleled by the changes in heart rate which decreased only during CN infusion (115 +/- 29 bpm), compared to the BsLn value (169 +/- 44 bpm). Similarily, Ppw was significantly increased only during CN infusion (15.2 +/- 5.0), from the BsLn value (8.1 +/- 2.7 mm Hg). There were no significant changes in Psa between the experimental stages Table 1. There were significant increases in Ppa and pulmonary vascular resistance during CN infusion compared to BsLn Table 1.
CO did not significantly affect any metabolic or acid-base variable. VO2 was significantly decreased only during CN infusion (69 +/- 21 mL/min), compared to a BsLn value of 133 +/- 19 mL/min Figure 4. VCO2 also decreased only during CN infusion (103 +/- 22 mL/min), compared to BsLn (128 +/- 27 mL/min) but after stopping the CN infusion there was a significant overshoot in VCO2 at the Post15 measurement (155 +/- 19 mL/min). Respiratory exchange ratio increased during CN infusion because VO2 decreased more than VCO2.
During CN infusion, PVCO2 was significantly decreased (33.7 +/- 9.9 mm Hg; Figure 5) compared to postinfusion stages (45.2 +/- 9.4 mm Hg at Post15). Compared to BsLn (7.31 +/- 0.07), pHv did not significantly decrease until Post15 (7.11 +/- 0.13) and recovery did not occur until Post75. The venous lactate significantly increased during CN infusion (4.7 +/- 2.5 mM) and remained above BsLn (1.2 +/- 0.7 mM) until Post75.
From BsLn to CO inhalation, PVO2 significantly decreased from 50.3 +/- 8.2 to 31.6 +/- 16.4 mm Hg while PaO2 did not change Figure 6. Then, during the CN infusion, PaO2 and PVO2 both significantly increased. From BsLn to CO inhalation, arterial O2 content (CaO2) decreased from 15.7 +/- 4.2 to 10.0 +/- 2.5 mL O2/100 mL blood (P < 0.01) and then increased during CN infusion to 13.0 +/- 3.5 mL O2/100 mL blood (P < 0.01). The changes in mixed venous O (2) content (CVO2) paralleled those of CaO2. From a BsLn value of 988 mL O2/min, oxygen delivery (QO2) steadily decreased to a low value during CN infusion (400 +/- 124 mL O2/min, P < 0.05). By Post15, QO2 had recovered to near BsLn levels.
At BsLn, sagittal sinus blood PO2 was 6.6 +/- 2.4 mm Hg lower than PVO2, PCO2 was 2.4 +/- 2.2 mm Hg higher than PVCO2, and pH was 0.02 +/- 0.01 units lower than pHv. At Post75, lactate in sagittal sinus blood was slightly but significantly higher (0.2 +/- 0.2 mM) than the value in mixed venous blood, compared to no differences at BsLn.
In this canine model of combined CO and CN poisoning, there were two major findings. First, despite significant CO poisoning (peak COHb = 46% of total Hb) with attendant decrease in blood O2 content, CO had essentially no affect on any hemodynamic or metabolic variable. Second, despite severe depression of most variables during the CN infusion, critical hemodynamic and metabolic function (Q (T) and VO2) had recovered significantly within 15 min after stopping the infusion. This recovery, coupled with the short t1/2 of CN in blood, suggests that the first important factor to help a fire victim with combined CO and CN poisoning is cessation of toxic exposure. Most treatments, especially after delayed diagnosis, would arrive late.
The uptake of CO followed a steep, single exponential function with t (1/2) of 50 s. Such fast absorption is similar to other reports  and underlines the danger of CO exposure in fires. The decrease in COHb during air ventilation also followed a single exponential decay. However, we determined an elimination t1/2 of 114 min, much shorter than other reports . In our study, concurrent CN poisoning was present but should not shorten the elimination time of CO.
That a single exponential function completely accounted for the CO elimination after peak COHb concentration suggests that CO was quickly distributed to the tissues. By administering a specific molar amount of CO to each dog, we could predict an amount of COHb produced if all of the CO remained bound to Hb. We found that one-third of CO was distributed to tissues other than Hb, such as myoglobin [17,18]. Studies that induced CO poisoning by the inhalation of a gas mixture containing a fixed CO percentage [4,7,11] could not measure the total administered dose.
In this study, CO poisoning resulted in significant decreases in blood O2 content and PVO2. However, no significant changes resulted in any other hemodynamic or metabolic variable. Yet, we induced significant CO poisoning. The peak level of 46% COHb is similar to values reported in fire victims [1,3] and in animal studies of CO poisoning [7,11].
We chose an infusion rate of KCN (0.072 mg centered dot kg-1 centered dot min-1) that was used previously in dogs [5,13]. Inspection of Figure 2 reveals that we never reached steady state. Blood CN concentration progressively increased until the CN infusion was stopped. Thus, a distribution phase occurred during the first 20 min after stopping the infusion, as CN diffused out of the extravascular compartment. Over the next 50 min, the elimination t1/2 was 129 min, somewhat longer than other reports [1,3]. Thus, significant CN levels persisted after the critical depression of hemodynamic function and metabolism had significantly recovered.
During the CN infusion, there was a 52% decrease in QT while Psa did not significantly change. That heart rate decreased by 32% and Ppw increased by 7 mm Hg suggests that CN directly depressed myocardial function. Other reports support generalized cardiovascular depression  and cardiac rhythm disturbance  resulting from CN intoxication.
The 48% decrease in VO2 occurred as aerobic metabolism was depressed during the CN infusion. Anaerobic metabolism was signalled by increased lactate concentration during the CN infusion [6,13] that peaked 15 min after the infusion stopped. Interestingly, we did not detect significant venous acidosis until 15 min after stopping the CN infusion. During the CN infusion, the 20% decrease in tissue VCO2 tended to decrease PVCO2, which helped to maintain a normal pH. By 15 min after stopping the CN infusion, VCO2 recovered to levels higher than BsLn, significantly increased PVCO2, and contributed to the decrease in pH. In this model of combined CO and CN poisoning, lactic acidosis persisted at least 25 min after stopping the CN infusion, due to some combination of oxygen debt and prolonged toxic effect of CN.
At BsLn, the high VO2 of the brain  resulted in decreased PO2 and pH and increased PCO2 in the sagittal sinus blood, relative to mixed venous measurements. When CN was present, gas exchange and metabolic measurements in sagittal sinus blood were similar to the rest of the body (mixed venous blood measurements). Thus, in this study, the brain was not over-represented as a target organ for CN effect, relative to the entire body.
The value of oxygen therapy, mechanical ventilation, and other supportive care is well established [3,9]. Oxygen will increase the elimination of CO and can enhance the specific treatment of CN [13,19,20]. However, the indications for specific therapy for the CN component of the poisoning are controversial . The clinical diagnosis of CN poisoning may be delayed [1,9] and the half-life of CN in blood is short. Thus, current specific treatments for CN (sodium thiosulfate and induction of methemoglobinemia) may be administered too late since their mechanism of action is in the extracellular space . Furthermore, therapeutic agents, such as the nitrites, can be even dangerous, as the induction of methemoglobinemia further reduces the oxygen-carrying capacity of blood, already reduced by the presence of COHb [11,12].
Several findings of this study are relevant to the treatment of CN poisoning. First, by 15 min after stopping the CN infusion, critical hemodynamic (QT) and metabolic (VO2) function had normalized with only ventilatory support. Second, lactic acidosis persisted at least 25 min after stopping the CN infusion. Third, the CN elimination t1/2 was 129 min so that significant CN was present in blood at least 25 min after stopping the infusion. Accordingly, we suggest that after extraction of a victim from a fire, administration of oxygen and support of ventilation will facilitate the return of critical cardiovascular and metabolic function, probably before any specific therapy for CN poisoning could be given. However, CN is still present in the body in significant levels with concurrent lactic acidosis. Conceivably, persistence of CN toxicity may be harmful to sensitive target organs, especially the brain , analagous to the long-term neuropsychiatric sequelae reported after CO poisoning . Thus, further studies are necessary to address the postexposure efficacy of cyanide antidotes, including thiosulfate [5,6], hydroxocobalamin [3,6], or stromafree metHb [9,12] during combined CO and CN poisoning.
The authors thank H. HajYousif and A. Montano for technical assistance and Ohmeda Corporation for providing the mass spectrometer.
1. Clark CJ, Campbell D, Reid WH. Blood carboxyhaemoglobin and cyanide levels in fire survivors. Lancet 1981;1:1332-5.
2. Mohler SR. Air crash survival: injuries and evacuation toxic hazards. Aviat Space Environ Med 1975;46:86-8.
3. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761-6.
4. Norris JC, Moore SJ, Hume AS. Synergistic lethality induced by the combination of carbon monoxide and cyanide. Toxicology 1986;40:121-9.
5. Christel D, Eyer P, Hegemann M, et al. Pharmacokinetics of cyanide in poisoning of dogs, and the effect of 4-dimethylaminophenol or thiosulfate. Arch Toxicol 1977;38:177-89.
6. Ivankovich AD, Braverman B, Kanuru RP, et al. Cyanide antidotes and methods of their administration in dogs: a comparative study. Anesthesiology 1980;52:210-6.
7. Pitt BR, Radford EP, Gurtner GH, Traystman RJ. Interaction of carbon monoxide and cyanide on cerebral circulation and metabolism. Arch Environ Health 1979;34:354-9.
8. Moore SJ, Ho IK, Hume AS. Severe hypoxia produced by concomitant intoxication with sublethal doses of carbon monoxide and cyanide. Toxicol Appl Pharmacol 1991;109:412-20.
9. Kulig K. Cyanide antidotes and fire toxicology [editorial]. N Engl J Med 1991;325:1801-2.
10. Sylvester DM, Hayton WL, Morgan RL, Way JL. Effects of thiosulfate on cyanide pharmacokinetics in dogs. Toxicol Appl Pharmacol 1983;69:265-71.
11. Moore SJ, Norris JC, Walsh DA, Hume AS. Antidotal use of methemoglobin forming cyanide antagonists in concurrent carbon monoxide/cyanide intoxication. J Pharmacol Exp Ther 1987;242:70-3.
12. Ten Eyck RP, Schaerdel AD, Ottinger WE. Comparison of nitrite treatment and stroma-free methemoglobin solution as antidotes for cyanide poisoning in a rat model. J Toxicol Clin Toxicol 1985;23:477-87.
13. Klimmek R, Roddewig C, Fladerer H, Weger N. Cerebral blood flow, circulation, and blood homeostasis of dogs during slow cyanide poisoning and after treatment with 4-dimethylaminophenol. Arch Toxicol 1982;50:65-76.
14. Thomas LJ, Jr. Algorithms for selected blood acid-base and blood gas calculations. J Appl Physiol 1972;33:154-8.
15. Westley AM, Westley J. Voltametric determination of cyanide and thiocyanate in small biological samples. Anal Biochem 1989;181:190-4.
16. Glantz SA. Primer of biostatistics. New York: McGraw-Hill, 1981:265-77.
17. King CE, Dodd SL, Cain SM. O2
delivery to contracting muscle during hypoxic or CO hypoxia. J Appl Physiol 1987;63:726-32.
18. Coburn RF. Mechanisms of carbon monoxide toxicity. Prev Med 1979;8:310-22.
19. Way JL, Gibbon SL, Sheehy M. Cyanide intoxication: protection with oxygen. Science 1966;152:210-1.
20. Isom GE, Way JL. Effects of oxygen on the antagonism of cyanide intoxication: cytochrome oxidase, in vitro. Toxicol Appl Pharmacol 1984;74:57-62.
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21. Smith JS, Brandon S. Morbidity from acute carbon monoxide poisoning at three-year follow-up. Br Med J 1973;1:318-21.