Alterations in hemostasis associated with hyperthermia in a canine model.

Use of hyperthermia in the treatment of cancer and viral infection has received renewed interest. However, the in vivo relationship between hyperthermia and direct versus indirect effects upon hemostasis are incompletely defined, although we do know that disseminated intravascular coagulation (DIC) is a common sequel to heat stroke. The purpose of the present study was to more precisely define the relationship between hyperthermia and derangements of hemostasis, thereby providing a guideline for the development of safe hyperthermia treatment regimens. The present investigation examined the in vivo effects of high-grade whole-body hyperthermia (WBH) (42.5 degrees C, 90 min) on hemostasis in a canine model. Induction of hyperthermia via extracorporeal circulation of heated blood (ECC-WBH) caused thrombocytopenia, increased plasma fibrin degradation products (FDPs), prolonged clotting times, increased serum liver enzymes, and evidence of spontaneous bleeding. However, when WBH was induced by peritoneal lavage (PL-WBH), transient thrombocytopenia was the only significant alteration. Temporal correlation between hemostatic alterations and elevations in serum alanine aminotransferase (ALT) levels in the ECC-WBH treatment group suggested that liver injury is responsible, at least in part, for the coagulopathy associated with high-grade hyperthermia and that in the absence of liver injury, identical degrees of hyperthermia cause only incidental decreases in platelet numbers.

Acid-base regulation, alpha-stat, and the emperor's new clothes.

Considerable time and effort have been expended to determine the most appropriate technique for management of a patient's acid-base status during hypothermic cardiopulmonary bypass. A critical question is whether to maintain plasma pH at 7.4 regardless of temperature (pH-stat) or to permit a relative alkalosis as the patient is cooled (alpha-stat). Until recently, there has been a remarkable lack of evidence in the literature for a consistent physiological benefit provided by one protocol over the other. The alpha-stat versus pH-stat controversy has taken on the characteristics of the emperor's new clothes, with alpha-stat winning by default because of theoretical arguments and because it was technically easier to perform. Part of the explanation is the realization that cellular mechanisms are capable of maintaining intracellular pH despite fluctuations in extracellular conditions. The prevailing plasma pH does have strong influence over cerebral blood flow, even to the point of overriding normal autoregulatory mechanisms. Recent evidence suggests that cerebral blood flow variations between alpha-stat and pH-stat conditions have important implications for patient outcomes.

Transduction dynamics of intrapulmonary CO2 receptors.

We have developed a functional model for quantitatively characterizing the transduction dynamics of the intrapulmonary CO2 receptors (IPC) in the snake lung. The model was based on experiments in which the neural discharges of several IPCs were recorded in response to abrupt step changes in CO2 concentration. Initial attempts to model the transduction dynamics linearly proved inadequate, although the linear model captured gross features such as rate sensitivity and the existence of two time constants in the adaptation time-course. However, with the incorporation of two static nonlinear features, namely, thresholding and preferential directionality of the rate-sensitive component, it was possible to account for over 80% of the total variation in the data. The model produced accurate predictions of IPC responses to other inputs, such as pseudorandom binary changes in CO2. The model also allows the prediction of IPC discharge in spontaneous breathing given measurements of lung CO2 concentration, and may serve as a starting point for further studies of transduction mechanisms at the cellular level.

Non-destructive evaluation of membrane lung gas exchange performance.

This paper describes a method of evaluating the gas exchange effectiveness of hollow fiber oxygenators utilizing gas on both sides of the membrane. The goal of the study was to develop an evaluation technique which was accurate, reliable, and did not harm or contaminate a new, sterile oxygenator. Three pediatric oxygenators were tested and compared: the Medtronic Minimax Plus, the Terumo Capiox 320, and the Sorin Masterflo 34 (all with rated blood flows of 2-2.5 L/min). Gas entering the "blood" side was a mixture of CO2, O2, and N2 in a mixture matching typical venous blood partial pressures. The "blood" flows used were 0.5, 1, 1.5, or 2 L/min. Gas entering the gas port had an FiO2 of 0.4 flowing at 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 L/min. Fractional contents of CO2 and O2 at all inlets and outlets were determined using a gas analyzer and converted to partial pressures. Efficacy indices and gas transfer rates were calculated and compared. Of the devices studied, the Masterflo 34 had the highest gas transport rates and effectiveness followed by the Minimax-Plus and the Capiox 320. Reversing the direction of the flow through the "blood" phase of the Minimax-Plus greatly changed its gas exchange effectiveness. The techniques described in this study should allow for a more uniform and consistent evaluation of gas exchange by membrane lungs which can be made inexpensively and relatively quickly. In addition, these methods should allow manufactures to evaluate gas exchange effectiveness and transfer rates of individual units during production as well as reduce the complexity involved when evaluating newly developed oxygenators.

Necrotizing tracheobronchitis (NTB) following high frequency ventilation: role of an angiotensin converting enzyme inhibitor.

The purpose of this investigation was to study the effect of an angiotensin converting enzyme inhibitor (enalaprilat) on the morphologic manifestations of experimentally induced necrotizing tracheobronchitis (NTB). Twenty piglets were anesthetized before saline lung lavage. High frequency flow interrupter (HFFI) ventilation was used with a strategy known to produce NTB. Animals were randomly assigned to receive IV enalaprilat 0.1 mg/kg (ENP-Hi), enalaprilat 0.01 mg/kg (ENP-Lo), or saline (C). After 8 hours of ventilation, the piglets were sacrificed. Total airway injury scores (mean +/- S.D.) were 1.2 +/- 0.7 for ENP-Hi, 0.2 +/- 0.2 for ENP-Lo, and 21.3 +/- 16 for group C. Enalaprilat minimizes NTB lesions in neonatal piglets exposed to high frequency oscillatory ventilation. Although the origin of NTB is multifactorial, airway mucosa ischemia may play an important role. Enalaprilat may compensate for the reduction of mucosal blood flow by limiting formation of angiotensin II and/or preventing degradation of bradykinin.

Does the employed technique of endotracheal extubation reduce the risk of aspiration?

Aspiration of gastric contents continues to be one of the most serious complications of general anesthesia. Laryngeal competence may be reduced immediately following endotracheal extubation, which may increase the risk of aspiration. An evaluation research design was used in 20 adult canines to compare the techniques of positive pressure extubation and extubation at the height of inspiration employing radiopaque barium. Evaluation of radiographs from both groups revealed that no aspirate of barium was detected in the tracheobronchial trees of any of the dogs. This study establishes that there is no difference in the risk of aspiration following endotracheal extubation using the canine model regardless of the clinical technique employed.

Necrotizing tracheobronchitis following high frequency ventilation: effect of hydrocortisone.

A piglet model of acute respiratory failure was used to determine whether necrotizing tracheobronchitis (NTB) produced during high-frequency pneumatic flow interrupter (HFFI) ventilation could be attenuated by prior administration of 2 mg/kg hydrocortisone IV. Fourteen piglets (means age 3.6 days, means wt 1.4 kg) were anesthetized and paralyzed before saline lung lavage. The animals were randomly assigned to either placebo (P) or hydrocortisone (H) group. Continuous HFFI (10 Hz) was interrupted five times per minute by a 1-second deflationary pause. All animals were kept on 1.0 FI02 with ventilators adjusted to maintain adequate arterial blood gases. Airway pressures were similar for both groups. After 8 hours of ventilation the animals were sacrificed and their lungs inflated with formalin to 40 cm H2O. Sections were obtained from trachea, carina, main stem, and peripheral bronchi. A total airway injury (TAIS) was calculated by a pathologist unaware of treatment assignment. There was a significant difference (p less than 0.01, Wilcoxon rank sum) in TAIS scores between P (means 21.3) and H (means 7.8). In five out of seven P animals and in one out of seven H animals, NTB was severe and extended to the hilar bronchi. Although NTB is multifactorial in origin, the prior use of hydrocortisone may decrease the severity and extent of lesions by modifying the inflammatory response to this specific airway injury.

Effect of direct mechanical ventricular assistance on myocardial hemodynamics during ventricular fibrillation.

Direct mechanical ventricular assistance (DMVA) is a method of biventricular circulatory support that employs a pneumatic device to apply both systolic and diastolic forces directly to the ventricular myocardium. This study investigated the effects of DMVA on myocardial hemodynamics when applied after a prolonged cardiopulmonary arrest. Seven swine weighting 28.3 +/- 2.5 kg were instrumented for regional myocardial blood flow (MBF) measurements using tracer microspheres. Ventricular fibrillation was then induced. After 10 min of ventricular fibrillation, CPR was initiated for 3 min. DMVA was then applied through median sternotomy. Defibrillation was attempted after 3.5 min of DMVA. If unsuccessful, DMVA was instituted for another 17.5 min and a subsequent defibrillation attempt was made. Arterial oxygen content (CaO2), coronary sinus oxygen content (CcSO2), myocardial oxygen delivery/consumption (mDO2/mVO2), extraction ratio (ER), and endocardial/epicardial blood flow ratio (EN/EP) were determined during CPR, during the initial application of DMVA (DMVA1), and after the subsequent 17.5 min of DMVA in those animals not initially defibrillated (DMVA2). Three of the seven animals were successfully defibrillated during DMVA1. After the additional 17.5 min of DMVA, only one other animal was defibrillated. There was a significant improvement in CaO2, CcSO2, MBF, mDO2, mVO2, ER, and EN/EP after DMVA1 compared to CPR. Only mVO2 and ER improved significantly after DMVA2. These findings support the concept that physical diastolic augmentation may improve myocardial hemodynamics when DMVA is applied during cardiac arrest.

Comparison of conventional and high-frequency ventilation in piglets after lung lavage.

A piglet model of respiratory failure was used to compare airway pressures required for adequate gas exchange by a conventional positive pressure ventilator (CMV) and a high-frequency pneumatic flow interrupter (HFFI). Twelve newborn piglets (age means = 3.8 days and weight means = 1.4 kg) were given saline lung lavages after receiving intravenous Ketamine and Pavulon. Femoral and jugular vessels were catheterized for measurements of aortic and pulmonary blood pressures and gases, cardiac output, hematocrit, glucose and for the infusion of fluids. Airway pressures were measured 5 mm above the distal tip of the endothracheal tube. Lung lavage resulted in decreased static compliance and a twofold increase in pulmonary shunting. Following lavage the animals were kept on 100% oxygen and randomly assigned to either CMV (30/min) or HFFI (600/min) ventilation and thereafter were switched every 30 minutes to the alternate mode. Inspiratory duration was 33% of the total respiratory cycle during CMV and 30-50% for HFFI. Sixteen pairs of data comparing both ventilator modes were used. Blood gases, cardiovascular variables, alveolar-arterial oxygen gradient, and pulmonary shunting were not different with either ventilator. Positive end-expiratory pressure (5.3 and 5.6 cm H2O) and mean airway pressure (12.5 and 11.9 cm H2O) were equal for CMV and HFFI, respectively. Peak inspiratory pressure was significantly lower for HFFI (23.1 +/- 3.7 SD cm H2O) than for CMV (30.4 +/- 5.5 SD cm H2O). The lower peak inflation pressure required during HFFI ventilation may reduce the potential for lung rupture.

Oxygen consumption during spontaneous ventilation with acute lung injury in anesthetized pigs.

Acute lung injury causes a restrictive pulmonary defect, decreases lung compliance, and increases the work of breathing. We wished to determine the oxygen cost of the increased elastic work of breathing associated with acute lung injury. Extracorporeal venous circulation with a membrane lung was used to extract CO2 and to induce apnea in 14 anesthetized pigs. Data were collected during 4 experimental states: during spontaneous ventilation and apnea when the animals' lungs were normal, and after acute lung injury developed because of oleic acid administration. Acute lung injury decreased lung compliance from 101 +/- 79 (mean +/- SD) to 52 +/- 25 ml/cm H2O (p less than 0.04), and increased the elastic work of breathing from 700 +/- 590 to 1,060 +/- 630 ml.cm H2O (p = 0.01). During spontaneous ventilation, the increases in total O2 consumption and the O2 cost of breathing caused by acute lung injury were sufficiently small as to be undetectable, and, therefore, less than 3 to 4% of basal O2 consumption despite markedly increased elastic work and ventilatory power requirements. The increase in O2 consumption imposed by acute lung injury was small enough (less than 3 to 4% of total O2 consumption) that it appears to be clinically insignificant.

Verapamil increases the toxicity of local anesthetics.

The calcium channel blocker verapamil has, in addition to its other properties, been shown to be a local anesthetic. Its concurrent use in a patient undergoing regional anesthesia may, therefore, increase the potential risk for local anesthetic toxicity. To evaluate this possibility, the effect of verapamil on the median lethal dose (LD50) of lidocaine and bupivacaine in mice was determined. Immediate pretreatment with verapamil increased the mortality of mice given the LD50 dose of lidocaine to 74%, and in mice given the LD50 doses of bupivacaine, to 82%. In animals pretreated with verapamil and calcium chloride, the mortality associated with the administration of LD50 doses of lidocaine and bupivacaine decreased to 43% and 48%, respectively, thus returning the mortality rate back to the LD50 of the local anesthetics when administered alone. It seems that the combined administration of local anesthetic and verapamil results in a significant drug interaction: the resulting blockade of sodium and calcium channels apparently impairs membrane function to a greater degree than with either drug alone. Additional investigation is warranted, and caution should be exercised in giving verapamil to patients during regional anesthesia. Should an adverse drug interaction ensue, the administration of calcium may be beneficial.

Necrotizing tracheobronchitis following high-frequency ventilation: effect of lung deflation.

A piglet model of acute respiratory failure was used to determine whether necrotizing tracheobronchitis (NTB) reported during high-frequency pneumatic flow interrupter (HFFI) ventilation could be minimized by a different ventilatory strategy. Twenty-one piglets (mean age 3.8 days, average weight 1.4 kg) were anesthetized with ketamine and given Pavulon prior to saline lung lavage. Femoral vessels were cannulated for measurements of blood pressures, arterial blood gases (ABG), and fluid administration. Airway pressures were measured 5 mm above the endotracheal tube tip. To allow for lung deflation, HFFI (10 Hz) was programmed to pause for 1 sec either 5 (HFFI5) or 12 times per min (HFFI12). Seven animals were assigned to each of the treatment groups and to a conventional mechanical ventilation (CMV) control. All animals were kept on 1.0 FIO2 with ventilators adjusted to maintain ABG (pO2 = 50-100 mmHg and pCO2 = 30-40 mmHg). After 6 h of ventilation, the animals were sacrificed and their lungs inflated with formalin to 40 cm H2O. Sections were obtained from trachea, carina, mainstem, and hilar bronchi. An airway injury score (AIS) was calculated after "blinded" microscopic evaluation. There was no difference in total AIS between CMV (2.4) and HFFI12 (8.6) but a statistically significant difference (p less than 0.05) existed between CMV and HFFI5 (14.1). NTB was limited to the trachea during HFFI12 but extended down to the hilar bronchi during HFFI5. More frequent lung deflations reduce the severity and distribution of NTB during HFFI ventilation.

Cardiopulmonary response to extracorporeal venous CO2 removal in awake spontaneously breathing dogs.

The ventilatory response to a reduction in mixed venous PCO2 has been reported to be a decrease in breathing even to the point of apnea with no change in arterial CO2 partial pressure (PaCO2), whereas a recent report in exercising dogs found a small but significant drop in PaCO2 (F. M. Bennett et al. J. Appl. Physiol. 56: 1335-1337, 1984). The purpose of the present study was to attempt to reconcile this discrepancy by carefully investigating the cardiopulmonary response to venous CO2 removal over the entire range from eupnea to the apneic threshold in awake, spontaneously breathing normoxic dogs. Six dogs with chronic tracheostomies were prepared with bilateral femoral arteriovenous shunts under general anesthesia. Following recovery, an extracorporeal venovenous bypass circuit, consisting of a roller pump and a silicone-membrane gas exchanger, was attached to the femoral venous cannulas. Cardiopulmonary responses were measured during removal of CO2 from the venous blood and during inhalation of low levels of CO2. Arterial PO2 was kept constant by adjusting inspired O2. The response to venous CO2 unloading was a reduction in PaCO2 and minute ventilation (VE). The slope of the response, delta VE/delta PaCO2, was the same as that observed during CO2 inhalation. This response continued linearly to the point of apnea without significant changes in cardiovascular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of haloperidol on dopamine-induced increase in renal blood flow.

Increasing renal blood flow (RBF) by the administration of low-dose dopamine is one mechanism to increase urine output in oliguric patients. This response is mediated in part by stimulation of dopaminergic receptors in the kidney, which could be attenuated by the dopamine blocker haloperidol. We evaluated this interaction by administering both drugs in clinically used doses to six anesthetized mongrel dogs. A dopamine regimen of 2.5 micrograms/kg/min significantly increased RBF along with cardiac output and stroke volume. Simultaneous administration of haloperidol 50 micrograms/kg iv did not influence the ability of low-dose dopamine to increase RBF. Although haloperidol is an antagonist of dopaminergic receptors, the increase in RBF associated with low-dose dopamine is maintained when intravenous haloperidol is concurrently administered to dogs.

Elevation of carcinoembryonic antigen in cerebrospinal fluid among patients with meningeal carcinomatosis.

The concentration of carcinoembryonic antigen (CEA) in cerebrospinal fluid (CSF) was determined by using an enzyme immunoassay for 204 patients with various nonneoplastic neurologic disorders, 8 patients with systemic infectious diseases, 19 patients with systemic neoplastic diseases without involvement of the nervous system, and 35 patients with neoplastic neurologic disorders. The highest CEA level in CSF among patients without neoplastic neurologic disorders was 0.6 ng/ml. Of 35 patients with neoplastic neurologic disorders, 10 had CEA levels in CSF that exceeded 0.6 ng/ml, the highest level being 70.5 ng/ml. All 10 patients had carcinomas. Among 14 patients with neoplastic meningitis, 5 of 8 patients with meningeal carcinomatosis had elevated CEA concentrations. Although the efficacy of the assay for CEA in CSF must be compared with that of other laboratory tests such as cytologic examination and the assay for beta-glucuronidase--and any potentially false-positive results should be ruled out by determination of the serum CEA level--the CEA concentration in CSF can be used as an adjunctive diagnostic procedure for detection of meningeal carcinomatosis.

Assay for beta-glucuronidase in cerebrospinal fluid: usefulness for the detection of neoplastic meningitis.

The specificity and sensitivity of the assay for beta-glucuronidase in cerebrospinal fluid were evaluated to determine the usefulness of this test for the detection of neoplastic meningitis. The enzyme activity was first measured in cerebrospinal fluid from 131 patients with various disorders and was then prospectively measured in cerebrospinal fluid from 30 patients with cytologic results that were positive for or suggestive of malignant disease. Within the first group, elevated levels of beta-glucuronidase were found only among patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with positive cytologic results, 13 had elevated beta-glucuronidase activities. Elevated values were more frequent among patients with adenocarcinoma (75%) and myelogenous leukemia (60%). The patients with these two disorders also had the highest enzyme activities. The correlation of th beta-glucuronidase level with other cerebrospinal fluid values, including total protein, glucose content, and cell count, was not significant. The findings of this study indicate that measurement of beta-glucuronidase in cerebrospinal fluid can be used as an adjunctive diagnostic test for neoplastic meningitis. The results should be interpreted with caution, however, because of the possibility that the elevated enzyme levels may be due to acute or subacute bacterial or fungal meningitis.

Vasopressin supplementation in a porcine model of brain-dead potential organ donors.

The use of vasopressin to limit the polyuria of the brain-dead organ donor is a controversial subject. It is held that the associated vasoconstriction may result in ischemic damage to transplantable organs. However, the derangements in the intravascular--and thereby interstitial and intracellular--fluid and electrolyte balances associated with diabetes insipidus may lead to gross fluid shifts in the organ donor. Aggressive resuscitation with crystalloid solutions may aggravate these fluid shifts, contribute to the development of interstitial and intracellular edema, and ultimately result in cardiovascular failure and the rejection of the organs for transplantation. Theoretically, a minute amount of vasopressin is required for the maintenance of normal intravascular fluid and electrolyte balance, and it is best administered as a continuous i.v. infusion. We report on our study of an animal model of a brain-dead organ donor, in which polyuria, hypernatremia, and hyperosmolality developed. The administration of low-dose (2-10 microU/kg/min) vasopressin by continuous infusion maintained plasma sodium and osmolality in the normal range over the course of the experiments (24 hr) in the experimental group. Cardiovascular function remained stable in both control and experimental vasopressin-infusion) groups, with the only significant difference being a moderate rise in pulmonary artery pressure. It would appear that early low-dose vasopressin supplementation by continuous i.v. infusion may improve donor management. The maintenance of intravascular homeostasis may contribute to the quality and number of organs for transplantation.

Role of VCO2 in control of breathing of awake exercising dogs.

Steady-state ventilatory responses to CO2 inhalation, intravenous CO2 loading (loading), and intravenous CO2 unloading (unloading) were measured in chronic awake dogs while they exercised on an air-conditioned treadmill at 3 mph and 0% grade. End-tidal PO2 was maintained at control levels by manipulation of inspired gas. Responses obtained in three dogs demonstrated that the response to CO2 loading [average increase in CO2 output (Vco2) of 216 ml/min or 35%] was a hypercapnic hyperpnea in every instance. Also, the response to CO2 unloading [average decrease in Vco2 of 90 ml/min or 15% decrease] was a hypocapnic hypopnea in every case. Also, the analysis of the data by directional statistics indicates that there was no difference in the slopes of the responses (change in expiratory ventilation divided by change in arterial Pco2) for loading, unloading, and inhalation. These results indicate that the increased CO2 flow to the lung that occurs in exercise does not provide a direct signal to the respiratory controller that accounts for the exercise hyperpnea. Therefore, other mechanisms must be important in the regulation of ventilation during exercise.

Effects of small changes in PaO2 on the ventilatory response to CO2 infusion.

The steady-state ventilatory responses to CO2 inhalation and two levels of intravenous CO2 infusion were examined in chronic awake dogs. Responses were obtained for four treatments: 1) air breathing, in which arterial O2 tension (PaO2) increased during infusion; 2) normoxia, PaO2 maintained at control levels; 3) hypoxia, PaO2 = 70 Torr; and 4) hyperoxia, PaO2 = 160 Torr. In three dogs, the ventilatory responses were obtained for treatments 1, 2, and 4 and in an additional three dogs for treatments 2, 3, and 4. Analysis of the data by directional statistics indicates that the response to infusion was hypercapnic for all treatments, and the slope of the response (change in minute ventilation divided by change in arterial CO2 tension) was identical to that of CO2 inhalation. Also, the slopes of the responses for the low infusion rate, CO2 output (VCO2) = 50%, and the high infusion rate, VCO2 = 270%, were identical, which suggests that the CO2 response is not significantly curvilinear near the eucapnic region. Finally, changing PaO2 between 70 and 160 Torr had no significant effect on the response slopes. Thus the ventilatory response to CO2 infusion in the awake dog is a hypercapnic hyperpnea that is not due to ventilatory inhibition arising from an increase in PaO2.

Lengthening of inspiration by intrapulmonary chemoreceptor discharge in ducks.

The influence of avian intrapulmonary chemoreceptors (IPC) on inspiratory duration (TI) was tested by experimentally reducing their level of discharge for a single inspiration. The seven major air sacs of decerebrate or anesthetized ducks were cannulated with wide-bore tubing and then connected to a single clamped outlet. In self-ventilating animals, opening the sac line for a single inspiration caused the inspiratory discharge of 17 IPC to disappear and that of a further 7 to fall substantially; no IPC showed a rise in discharge, nor did the 6 presumed respiratory stretch receptors from which recordings were made. The reduction of IPC discharge was accompanied by a fall in TI rather than the rise required if IPC were to resemble mammalian pulmonary stretch receptors in their action on TI. We propose that in eupnea inspiratory IPC discharge prolongs inspiration.