David G. Penney

Acute carbon monoxide poisoning : animal models : a review

Animals have been used for well over a century in an attempt to understand the toxicology, physiology, and pathology of acute carbon monoxide poisoning. Whether the toxic effects of this gas result from primary hypoxia, as in hypoxic hypoxia to which it is frequently compared, or from direct tissue effects since it enters cells and binds to certain vital components, remains a point of controversy. Acute severe poisoning in man and animals affects primarily the cardiovascular and nervous systems, and frequently produces neurologic dysfunction. Morphologically, tissue damage is usually confined to the white matter. The root cause is at best poorly understood and major investigative efforts have been made toward its elucidation. Many studies with rats, cats and primates indicate a major role for CO-induced hypotension, which serves to compromise blood flow and exacerbate acidosis. The likely cellular mechanisms in this process are only now becoming apparent. This review critically examines the recent as well as a few older CO-animal studies. In scope, they fall into several broad categories: general cardiopulmonary effects, metabolic and tissue effects, general resistance (i.e. tolerance), effects on the central nervous system including blood flow, neurochemistry, morphology and behavior, and finally, experimental therapeutic approaches.

Comparison of the acoustic properties of six popular stethoscopes

This study evaluated stethoscope acoustics by using a sound frequency generator and an active artificial ear. Six popular, currently available stethoscopes were compared in their various modes involving bells, diaphragms, etc.: Littmann Classic II, Littmann Cardiology II, Littmann Master Cardiology, Hewlett-Packard Rappaport-Sprague, Tycos Harvey Triple Head, and Allen Medical Series 5A RPS Binaural. The transfer function was measured from 37.5-1000 Hz, the range where nearly all heart and lung sounds are found. Sound in the low-frequency range (37.5-112.5 Hz) was in most cases amplified by the bells and attenuated by the diaphragms; however, there were no significant differences. Both bells and diaphragms attenuated sound transmission in the high range, and this increased with frequency. The Tycos Harvey Triple Head ribbed diaphragm attenuated sound transmission to a significantly greater extent than the other diaphragms (P less than 0.01). The results show that the bell and diaphragm for a given stethoscope usually have different transmission characteristics, particularly at low frequencies. The Littmann Classic II is an exception. The Hewlett-Packard and Tycos Harvey stethoscopes showed the greatest differences in low frequency response between the bell and the diaphragm. While the differences found in sound transmission between stethoscopes were in most cases small, the Littmann Cardiology II, bell and diaphragm, appears to possess the best overall performance by this study design.

Stethoscope Acoustics and Cervical Auscultation of Swallowing

Frequency response characteristics of six popular stethoscopes are reported for the higher frequency range (to 3000 Hz) to supplement equivalent measurements for the lower frequencies (35–1000 Hz) published previously. Spectra of the sounds of swallowing from the throat, transduced with an accelerometer, demonstrate important frequency composition in this higher range. Two stethoscope models were found to have superior transmission characteristics for use in cervical auscultation of swallowing sounds.

Cardiomegaly due to myocyte hyperplasia in perinatal rats exposed to 200 ppm carbon monoxide

Exposure to carbon monoxide (CO) during the fetal and neonatal period was used to evaluate cardiac ventricular regional weight and myocyte growth response to an increased hemodynamic load. Date-mated Sprague-Dawley rats inhaled 200 ppm CO from day 7 of pregnancy until parturition; another group of pregnant rats inhaled room air. At birth, pups from these two groups were subdivided into four groups: (1) control group (AIR/AIR), that was maintained in room air in utero and post-partum; (2) AIR/CO group, which received CO only after birth; (3) CO/CO group, which received CO exposure in utero and post-partum; and (4) CO/AIR group, which received CO exposure in utero but was maintained in room air post-partum. Rats were removed from litters at selected intervals from birth to 28 days of age and used to determine regional ventricular weights and ventricular dry weights, and to obtain isolated myocyte preparations for measurement of cell size characteristics and allow calculation of cell numbers. Compared with AIR raised control animals, right ventricular weight was increased in animals exposed to CO during the fetal period. Post-natal CO exposure caused an increase in left ventricular weight. Heart weight to body weight ratio of animals exposed to CO post-natally only (AIR/CO) gradually increased to reach that of the CO/CO group by 12 days of age, while animals exposed to AIR post-natally following fetal CO exposure gradually decreased their heart weight to body weight ratio toward that of the control animals by 28 days of age. Binucleated cells first appeared at 4 days of age in all groups. Myocyte volume was similar in both groups at birth and increased from six through 28 days of age. Left ventricle plus septum and right ventricle cell volumes of the CO/CO group were smaller than the controls at 28 days of age in spite of heavier wet and dry weights in the CO-exposed rats. At birth, the CO-exposed animals had more myocytes in the RV compared to AIR-exposed controls. Carbon monoxide exposure after birth resulted in left ventricular myocyte hyperplasia. The results of this study indicate that increased hemodynamic load due to CO exposure during the fetal period results in cardiomegaly because of increased myocyte hyperplasia. This cellular response is sustained through the early neonatal period in animals exposed to CO both in utero and post-partum.

Frogs and turtles: Different ectotherm overwintering strategies

The ability of frogs and turtles to overwinter and to survive hypoxia and anoxia has long been a topic of interest. While data remains scant, the emerging picture shows fundamentally different approaches to overwintering in these two groups of ectotherms. Frogs are far more limited by availability of oxygen than are turtles, even at near-freezing ambient temperatures. The reasons for this probably involve the vastly greater cutaneous permeability of the former. With their extreme tolerance of anoxia and profound suppression of metabolism, overwintering in turtles should not be viewed as simply prolonged diving but rather as ectotherm hibernation. Their incredible diving capabilities are merely a spin-off of a successful overwintering strategy. The following discussion reviews the major physiological mechanisms involved in the overwintering strategies of these two ectotherm groups.

Cardiovascular, metabolic and neurologic effects of carbon monoxide and cyanide in the rat

Levine-prepared, female Sprague-Dawley rats were used to investigate the effects of carbon monoxide (CO) and cyanide (CN) on heart rate, blood pressure, hematocrit, body temperature, blood glucose, lactate, and neurologic function. Rats were exposed to either 2400 ppm CO, 1500 ppm CO, 4 mg/kg NaCN, or both 1500 ppm CO and 4 mg/kg NaCN for 90 min, followed by 4 h of room air recovery. Following exposure to 2400 ppm CO, rats exhibited a significant bradycardia which normalized by 2 h of recovery. All groups exhibited an initial hypotension which was either maintained or exaggerated during exposure in all but the rats exposed to CN, and which returned to pre-exposure values by 90 min. All groups experienced a significant hypothermia during the exposure period, with those in the 1500 ppm CO or the CN returning to initial values over the recovery period. The only significant change in hematocrit was due to 2400 ppm CO (4.1% increase). During exposure, all groups experienced an initial surge in glucose concentration which was maintained in all but rats exposed to 2400 ppm CO. The greatest hyperglycemic response resulted from the combination of CO and CN, whereas 2400 ppm CO produced the smallest. CN alone produced no significant rise in lactate concentration. However, lactate concentration in all other groups was significantly elevated during the exposure period, returning to initial values by 4 h of recovery. Lactate concentrations and neurologic deficit in rats exposed to 1500 ppm CO, when added to those rats treated with CN, closely approximated the lactate and neurologic deficit of the combination treatment. Neurologic deficit was greatest in rats exposed to 2400 ppm CO. While in most cases the responses of the rats to CO and CN differed whether the substances were administered alone or in combination, a synergistic relationship is not suggested. An additive or less than additive relationship is more likely.

Electrocardiographic responses to carbon monoxide and cyanide in the conscious rat

Carbon monoxide (CO) and cyanide (CN), commonly found in exhaust fumes and smoke, act as hypoxic agents in eliciting morbid and lethal effects. This study explored the effects of these two toxicants on the ECG in a controlled and well-characterized animal model. Levine-prepared awake female rats were treated with 1500 and 2400 ppm CO for 90 min, CN at 4 mg/kg, or 1500 ppm CO plus 4 mg/kg CN. As in past studies, CO initially induced hyperglycemia and many-fold increases in blood lactate concentration, and rebound increases in blood glucose during recovery. CN produced hyperglycemia, however, there was no glucose rebound, nor was there a significant increase in lactate. CN plus 1500 ppm CO produced glucose changes similar to that of CO alone. CO exposure also induced hypothermia and hypotension, while CN produced little change in these parameters. CO increased heart rate, while CN tended to decrease heart rate. PR interval was increased significantly 4.5-17.0 ms by exposure to CO, with or without combination with CN, while CN alone produced minimal change in the PR interval. QT interval was increased up to 20 ms by exposure to CO, with or without combination with CN. CN alone produced no change in the QT interval. T wave duration was increased up to 22.5 ms by exposure to 1500 ppm CO, with or without combination with CN. CN alone produced minimal changes in T wave duration. There were no changes in duration of the (Q)RS complex or of the R wave. QT interval lengthening was positively correlated with the decrease in systolic blood pressure (0-30 min, r = 0.657, P < 0.05; 0-60 min, r = 0.704, P < 0.05). Hypothermia was correlated with increase in lactate concentration (r = 0.73, P < 0.05) and with decrease in blood pressure (r = 0.69, P < 0.05). No correlation between body temperature and QT interval was observed. The results indicate that CO at the concentrations used in the Levine-prepared rat has major effects on the ECG in slowing AV conduction and ventricular repolarization. In contrast, CN at 4 mg/dl has little or no effect on either conduction or repolarization in this animal model. These findings are discussed in light of past animal and human studies.

NMDA receptor-blocker ketamine protects during acute carbon monoxide poisoning, while calcium channel-blocker verapamil does not.

Levine‐prepared, female, Sprague‐Dawley rats were used to investigate the possible protective effects of the NMDA receptor‐blocker anesthetic ketamine and the Ca2+ channel‐blocker verapamil (0.4 mg kg−1 ‘low dose’, and 1.0 mg kg−1 ‘high dose’) in rats during acute 2400 ppm carbon monoxide (CO) poisoning. Blood glucose and lactate concentrations, heart rate, mean arterial blood pressure (BP), body temperature (BT), neurological function and cerebral cortical water content were measured. In most cases glucose increased after 45 min and then fell to initial values after 90 min. Lactate concentration increased sharply during CO exposure in the saline and in the low‐ and high‐dose verapamil groups, while the lactate increase in rats given ketamine at 40 mg kg−1 was significantly lower than with saline. Lactate was also significantly lower in these rats after 90 min than in the high‐dose verapamil group. Lactate was normal in all four groups after 2 and 4 h of air recovery. Ketamine significantly lowered the heart rate prior to CO exposure, and the heart rate remained significantly below values for the saline and for the low‐ and high‐dose verapamil groups throughout CO exposure. The BP decreased in all groups during CO exposure, and the BP recovery which took place in all four groups was significantly more rapid in the ketamine group. Recovery from CO‐induced hypothermia was similar in the ketamine and saline groups, whereas rewarming tended to occur more slowly and less completely in the two verapamil‐treated groups. There were no significant differences in neurological function among the four groups, as assessed after 4 h of recovery. However, cerebral edema was significantly reduced by treatment with 40 mg kg−1 ketamine as compared with saline. Verapamil at neither the low nor the high doses was of significant benefit in this regard. No rat in the 40 mg kg−1 ketamine group died during CO exposure, whereas all deaths in the other groups took place during CO exposure. The use of higher and lower doses of ketamine suggest 40–80 mg kg−1 as most effective in suppressing lactate production; 40 mg kg−1 ketamine may be optimal with regard to survival. The results suggest that ketamine is beneficial, when administered before and during acute severe CO poisoning, in reducing blood lactate and cerebral edema and in improving BP recovery and survival. Verapamil, in contrast, appears to provide no benefits in these respects.

Temporary and lasting cardiac effects of pre- and postnatal exposure to carbon monoxide

Abstract Pregnant female rats inhaled 200 ppm CO for the last 18 days of gestation, and a portion of their young inhaled 500 ppm CO for an additional 29 days after birth. Body weight (BW) and litter size of the CO-exposed newborn were significantly lower than those of unexposed controls. Heart weight (HW) of the exposed newborn was significantly larger than the controls, as was also HW BW ratio. Hemoglobin concentration, hematocrit, and red blood cell count were significantly lower in the exposed newborn than in controls In young rats exposed to CO both pre- and postnatally, HW BW ratio was more than twice as large as that of unexposed controls at 14, 21, and 29 days after birth (statistically significant), while in young rats exposed only as fetuses HW BW ratio was only slightly higher than in controls at the same time intervals. The remaining rats in all three groups were allowed to mature to 105 days of age in room air, at which time they too were sacrificed. HW BW ratio of the pre- and postnatally exposed rats was significantly elevated above the same parameters for the controls and rats exposed to CO as fetuses only. The HW BW ratio of the latter two groups did not differ significantly from one another. Analysis of HW data using multiple exponential regression equations relating HW to BW, showed HW of the rats exposed to CO both pre- and postnatally to be 22% larger than predicted. The results suggest that fetal cardiomegaly induced by CO is entirely reversible, while neonatal exposure produces long-standing changes in HW.

Acute carbon monoxide poisoning in an animal model: the effects of altered glucose on morbidity and mortality.

An animal model in which the common carotid artery and the jugular vein serving one side of the brain are occluded by indwelling catheters has been used during the past few years to investigate acute carbon monoxide (CO) poisoning. This article reviews the recent research examining the pattern of changes in blood glucose concentration which results from CO exposure, and the manner in which altered glucose concentration alters neurologic outcome and mortality. At present it appears that either greatly depressed glucose or greatly elevated glucose during and/or after CO exposure increases morbidity and mortality. Cyanide (CN) poisoning, in contrast to CO, produces a different pattern of changes in blood glucose and lactate, and unlike CO, fails to slow cardiac AV conduction and ventricular repolarization. Through the use of magnetic resonance imaging and spectroscopic techniques, cerebral cortical edema and the changes in brain phosphagens have been assessed following CO poisoning in the rat. The published results as well as data from recent pilot studies are discussed in the light of our current understanding of CO toxicology.