Constant infusion of epinephrine, but not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs.

OBJECTIVE: Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). In this condition, most treatment guidelines have been anecdotally derived and no randomized clinical trials have been conducted. In the present study, we examined the time course of haemodynamic recovery in a canine model of AS when Epi was administered at the initiation of allergen challenge before fully developed shock had occurred. METHODS: Randomized, controlled, crossover studies were performed approximately 3-5 weeks apart in ragweed-sensitized dogs while the animals were ventilated and anaesthetized. Epi was administered by bolus intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.) routes and by continuous i.v. infusion (CI). The findings obtained in the Epi treatment (T) studies were compared with those found in a no treatment (NT) study. In the bolus studies, Epi was administered at 0.01 mg/kg, while in the CI study, the dose of Epi was titrated to maintain mean arterial pressure (MAP) at 70% of preshock levels. MAP, cardiac output (CO), stroke volume (SV), and pulmonary wedge pressure (Pwp) were determined over a 3 h period. RESULTS: In the CI study, haemodynamics (CO, MAP, and SV) were significantly higher than those measured in the NT study and the bolus studies over approximately the first hour of the study. In the CI study, the amount of Epi infused was significantly less than in the bolus studies. CONCLUSION: When administered at the initiation of allergen challenge, bolus treatment of Epi by i.m., i.v., or s.c. routes caused limited haemodynamic improvement in AS. In contrast, constant infusion of Epi at a lower total dose produced significant haemodynamic improvement. Within the limits of this anaesthetized canine model, the results suggest that CI should be the preferred route in the treatment of AS when this treatment option is available.

Lung volume reduction surgery for the treatment of severe emphysema: a study in a single Canadian institution.

OBJECTIVE: To evaluate lung volume reduction surgery (LVRS) and its effectiveness in improving pulmonary function, exercise capacity and quality of life in a population of emphysema patients referred to and screened in a single centre. DESIGN: A prospective case series. SETTING: A Canadian tertiary care hospital. PATIENTS: Patients with severe emphysema, significant dyspnea and impaired exercise capacity interfering with quality of life. INTERVENTIONS: Bilateral LVRS was performed through a median sternotomy. MAIN OUTCOME MEASURES: Pulmonary function tests (preoperative forced expiratory volume in the first second [FEV1], residual volume [RV]), 6-minute walk (6 MW) distance, quality of life (Medical Outcomes Study 36-item short-form health survey) and degree of dyspnea (Medical Research Council of Great Britain dyspnea scale and the baseline and transitional dyspnea indices) were assessed before LVRS and at 6 and 12 months after. RESULTS: Fifty-seven patients were assessed for LVRS, of whom 10 were selected for surgery. Homogeneous distribution of disease was the most common reason for exclusion. Of the 10 patients operated upon, 1 died of acute cor pulmonale on the fourth postoperative day and 1 died of recurrent exacerbations of chronic obstructive pulmonary disease and chronic respiratory failure at 315 days postoperatively. In the surviving patients, the mean preoperative FEV1 increased from 0.70 L before surgery to 0.90 L at 1 year, with a mean relative increase of 33.4%. The mean RV decreased from 5.57 L to 4.10 L, with a mean relative decrease of 27.6%. The 6 MW distance increased from 302.7 m to 356.9 m at 1 year, with a mean relative increase of 21.6%. Quality of life and degree of dyspnea were improved significantly at 1 year after LVRS. Of the 5 patients on oxygen at home before surgery, 4 were able to reduce their requirements but not to discontinue oxygen. CONCLUSIONS: LVRS is an effective palliative treatment for dyspnea and poor exercise tolerance in highly selected patients. Although the duration of palliation is unknown, our results show that improvements in pulmonary function, exercise, quality of life and degree of dyspnea are preserved over the first year. Only a minority of the patients screened were eligible for surgery. The 2 deaths in our series emphasize the need for even further delineation of selection criteria.

Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis.

PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.

Impaired hepatic extraction and increased splanchnic production contribute to lactic acidosis in canine sepsis.

In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear. We examined SLP and HLE in E. coli sepsis in dogs. We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups. The animals were studied while anesthetized and ventilated. During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD). During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs. None of the vasopressor treatments had a detrimental effect on SLP. These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction. Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.

Histamine H3 receptor blockade improves cardiac function in canine anaphylaxis.

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whether pretreatment with H1, H2, H3 receptor blockers, and cyclooxygenase and leukotriene pathway inhibitors was useful in preventing the depression in left ventricular (LV) contractility known to occur in this model. The dose of allergen was varied to produce similar degrees of shock between treatments. The animals were studied under pentobarbital anesthesia in which the treatment studies were approximately 3 wk apart. LV volumes were measured by sonomicrometric techniques. During challenge, mean arterial blood pressure (Pa), cardiac output (Q), and LV end-diastolic pressure (LVEDP) decreased approximately 50% compared with preshock values in all treatments. Histamine H3 receptor blockade was associated with higher heart rates (HR) and higher stroke work (SW) (p < 0.05) as compared with the other treatment studies. We conclude that histamine H3 activation by inhibiting adrenergic neural norepinephrine release contributes to cardiovascular collapse in AS.

Early but not delayed continuous arteriovenous hemofiltration improves cardiovascular function in sepsis in dogs.

OBJECTIVE: Continuous arteriovenous hemofiltration (CAVH) has been advocated as treatment to remove inflammatory mediators and thereby to improve hemodynamic parameters in sepsis. However, the results obtained with CAVH have been inconsistent. In a canine model of bacteremic Pseudomonas aeruginosa pneumonia, we tested the hypothesis that the time course of the institution of CAVH may be important in obtaining a beneficial treatment effect. METHODS: Two protocols were performed in phenobarbital-anesthetized dogs. In the early hemofiltration study (EHS), CAVH for 3 h was initiated 2 h post-pneumonia before mean arterial pressure (MAP) fell. In the late hemofiltration study (LHS), CAVH for 3 h was initiated at 5 h post-pneumonia when a decrease in MAP had already occurred. Hemodynamic measurements included cardiac output (CO), stroke volume (SV), and stroke work (SW). Myocardial depressant activity [filterable cardiodepressant substance (FCS)] found in plasma was assessed by bioassay at each measurement interval. RESULTS: In EHS, after 5 h of sepsis, SW, CO, and SV in the hemofiltered pneumonia group were higher as compared with the nonhemofiltered pneumonia group. In contrast, in LHS, no differences in hemodynamic parameters were found between the two pneumonia groups. In both EHS and LHS, plasma FCS activity was decreased to similar extents by CAVH. CONCLUSION: These results suggest the time course of institution of CAVH may be important in obtaining a beneficial treatment effect in sepsis.

Histamine H3 activation depresses cardiac function in experimental sepsis.

In the heart, histamine (H3) receptors may function as inhibitory presynaptic receptors that decrease adrenergic norepinephrine release in conditions of enhanced sympathetic neural activity. We hypothesized that H3-receptor blockade might improve cardiovascular function in sepsis. In a canine model of Escherichia coli sepsis, we found that H3-receptor blockade increased cardiac output (3.6 to 5.3 l/min, P < 0.05), systemic blood pressure (mean 76 to 96 mmHg, P < 0.05), and left ventricular contractility compared with pretreatment values. Plasma histamine concentrations increased modestly in the H3-blocker-sepsis group compared with values obtained in a nonsepsis-time-control group. In an in vitro preparation, histamine H3 activation could be identified under conditions of septic plasma. We conclude that activation of H3 receptors may contribute to cardiovascular collapse in sepsis.

Tumour necrosis factor-alpha, but not septic plasma depresses cardiac myofilament contraction.

PURPOSE: In sepsis, myocardial depression may be caused by mediators released as part of the inflammatory reaction, lumour necrosis factor alpha (TNF alpha) is one mediator that may contribute to this depression. In the present study, we contrasted the effects of TNF alpha and septic plasma fraction (SP) obtained from an E. coli model on contractile tension in intact and skinned canine ventricular trabecular (VT) preparations. The objectives were to determine whether SP or TNF alpha could impair contractile tension at the level of the myofilaments, and to determine the extent to which TNF alpha may account for myocardial depression found in E. coli sepsis. METHODS: Measurements of isometric tensions were made after TNF alpha and SP (10,000 to 30,000 MW fraction) were added to respective intact or skinned canine VT preparations. In the skinned preparation, trabeculae were chemically skinned with Triton X-100. RESULTS: Septic plasma caused a decrease in contraction in the intact preparation compared with preseptic plasma (50 +/- 7 vs 33 +/- 7%, P < 0.05), but had no effect in the skinned preparation. On the other hand, TNF alpha (30 ng.ml-1) caused an approximately 50% reduction in tension (29 +/- 2 mg vs 16 +/- 5 mg) in the skinned preparation (P < 0.05), but had no effect in the intact preparation. CONCLUSION: These results suggest that TNF alpha and SP act through different mechanisms. While SP requires an intact membrane, TNF alpha impairs function by a direct effect on the myofilaments.

Effects of anaphylaxis mediators on partitioned pulmonary vascular resistance during ragweed shock in dogs.

We examined the effect of anaphylactic shock on the longitudinal distribution of pulmonary vascular resistance (PVR) in ragweed-sensitized dogs in which PVR was partitioned into an upstream arterial component (Rus) and a downstream venous and capillary component (Rds). We also assessed whether Rus and Rds would be reduced by pretreatment with histamine H1- and H2-receptor blocking agents and with cyclooxygenase and lipoxygenase pathway inhibitors. Anesthetized animals were examined on separate occasions 3 wk apart in which one of the treatments was randomly given. The pulmonary arterial occlusion technique was used to determine segmental pressure drops. During ragweed challenge, PVR increased approximately 4 times compared with the preshock value (3.04 vs. 12. 07 mmHg . l-1 . min; P < 0.05). Although both Rus and Rds increased postshock, the greatest relative increase occurred in Rds. None of the treatments reduced partitioned resistances compared with no treatment. Our results show that, under conditions of anaphylactic shock, increases in Rus and Rds could not be ascribed to release of histamine or products of the cyclooxygenase and lipoxygenase pathways.

Effect of bolus epinephrine on systemic hemodynamics in canine anaphylactic shock.

OBJECTIVE: Epinephrine (Epi) is considered to be the drug of choice for anaphylactic shock (AS). However, the benefit of this drug on improving systemic hemodynamics in AS has never been shown. We used a canine ragweed model of AS to determine if an intravenous bolus of Epi hastened the recovery of hemodynamics and modified mediator release (Med) compared with no treatment (NT). METHODS: In one protocol (n = 8), the effects on hemodynamics of two intravenous doses of Epi (0.01 and 0.025 mg/kg) were examined for 3 h postshock in respective studies approximately three weeks apart under pentobarbital anesthesia in the same animal. In five other dogs, left ventricular (LV) mechanics were additionally determined by sonomicrometric techniques to determine changes in contractility as defined by the preload recruitable stroke-work (SW) relationship. RESULTS: Compared with NT values, Epi treatments produced only transient increases in mean arterial pressure (MAP) and cardiac output (CO) post-challenge. By 20 min postshock, CO in the Epi studies were generally lower (p < 0.05) and BP was not different from NT values. With Epi treatment, SW was reduced for a given LV end-diastolic volume compared with the control study. Epi treatments also caused relatively higher plasma thromboxane B2 concentrations postshock. CONCLUSION: Our findings indicate that, when given immediately postshock, bolus-Epi did not hasten recovery and caused impairment in LV mechanics in canine AS.

Mechanism of lobar alveolar pressure decline during forced deflation in canine regional emphysema.

A canine model of unilobar papain-induced emphysema was used to examine the extent to which differences in alveolar pressures (PA) would develop between an emphysematous right lower lobe (RLL) and normal left lower lobe (LLL) during forced vital capacity (FVC) deflation. RLL and LLL PA (PARLL and PALLL, respectively) were measured by the alveolar capsule technique. During forced deflation, PA and lobar flows were determined between 95 and 20% FVC. A choke point common to both lower lobes was observed at > 40% FVC. The results showed that deflation compliance (C) was altered for the RLL such that <90% lobar vital capacity, CRLL > CLLL, whereas >90% lobar vital capacity, CRLL < CLLL. At 95 and 90% FVC, the initial RLL PA decline was greater than that for the LLL (P < 0.05). However, large differences in PA were prevented because of the effect of interdependence of regional expiratory flow (IREF). IREF caused a relative decrease in RLL flows and increase in LLL flows that limited PA differences. Between 80 and 50% FVC, as CRLL became greater than CLLL, and because of the initial effect of IREF, PARLL was approximately PALLL. At < and = 40% FVC, without IREF, lobar differences in PA widened. These findings indicate that IREF may affect the dynamics of flow limitation in regional lung disease.

Effect of continuous arteriovenous hemofiltration combined with systemic vasopressor therapy on depressed left ventricular contractility and tissue oxygen delivery in canine Escherichia coli sepsis.

BACKGROUND: In a previous study, we showed that continuous arteriovenous hemofiltration (CAVH) reversed the depression in left ventricular (LV) contractility in canine Escherichia coli sepsis by the removal of a circulating substance the molecular weight of which is less than 30,000. Despite the normalization of LV contractility, however, we were unable to demonstrate an improvement in systemic arterial blood pressure (BP), presumably because the mechanisms underlying the depression in LV contractility and the decrease in BP are different in sepsis. In the current study, we examined the effect of combined treatment with CAVH and the alpha-adrenergic agonist phenylephrine on LV mechanics and tissue oxygen delivery in our canine E. coli model. METHODS: Measurements were obtained at baseline (condition B), after 4 h of sepsis (condition S), and after 2 h of CAVH and phenylephrine (condition P) (total of 6 h of sepsis). During P, phenylephrine was infused to restore BP to that found at baseline. The slope of the end-systolic pressure-dimension relation was used as the index of LV contractility; LV anterior-posterior dimensions were measured by sonomicrometry. RESULTS: During combined CAVH and phenylephrine treatment, the decrease in the slope of the end-systolic pressure-dimension relation otherwise observed at S was reversed. The slope (mean +/- SD) was 57.5 +/- 32 mmHg/mm at B versus 22.2 +/- 8 mmHg/mm at S (P < 0.05, B vs. S) versus 62 +/- 37 mmHg at P (P < 0.05 S vs. P) (analysis of variance). Mean BP was restored to that found at B (123 +/- 19 mmHg versus 82 +/- 14 mmHg (P < 0.05 B vs. S) versus 116 +/- 27 mmHg (P < 0.05 S vs. P). Combination treatment with CAVH and phenylephrine also improved stroke volume (39.3 +/- 13.5 versus 32 +/- 8 versus 44 +/- 12 ml) and tissue oxygen delivery during P compared with results obtained when phenylephrine was given alone. CONCLUSIONS: Our study offers a rationale for the combined use of phenylephrine and CAVH in the reversal of cardiac depression and hypotension in sepsis.

Altered left ventricular chamber stiffness and isovolumic relaxation in dogs with chronic pulmonary hypertension caused by emphysema.

BACKGROUND: In chronic obstructive lung disease, a right to left ventricular septal shift that occurs as a consequence of right ventricular pressure overload is the usual mechanism given to explain a decrease in left ventricular (LV) diastolic performance. The purpose of the present study was to examine the extent to which this mechanism could account for a decrease in LV diastolic function in a canine model in which pulmonary artery pressure was elevated to a level found in human disease. METHODS AND RESULTS: Severe emphysema was produced in dogs by repeated instillations of the enzyme papain into the lung. To assess LV diastolic function, we used sonomicrometry, in which three pairs of subendocardial crystal transducers were implanted along the three orthogonal axes of the LV. LV end-diastolic dimensions and pressure-strain relations along the three axes, as well as the time constant of LV isovolumic relaxation (T), were measured before (baseline) and after 1 year of emphysema (post-1-year study). The results showed that after 1 year of pulmonary hypertension, LV pressure-strain relations were decreased along the septal-lateral and anterior-posterior axes, but a right to left ventricular septal shift was not detected. The relation of average midwall circumferential stress to midwall circumferential strain was used to describe the intrinsic compliance of the LV. The results showed that myocardial stiffness increased in emphysema but that chamber volume was not reduced. At the post-1-year study, T was abnormally increased in the emphysema group in response to augmented preload and afterload compared with preemphysema measurements. CONCLUSIONS: We conclude that mechanisms other than ventricular interdependence may be operative in leading to altered LV diastolic filling in chronic emphysema.

Does pentobarbital anesthesia depress left ventricular contractility in dogs?

Although pentobarbital sodium (NP) anesthesia has been shown to depress left ventricular (LV) contractility in dogs, measurements of LV contractility in previous studies have been made soon after a bolus of NP was given when serum concentrations would be extremely high. In this study, we compared indexes of LV contractility during awake and anesthetized conditions. During anesthesia, measurements were obtained 1 h after an intravenous bolus of NP was given when serum concentrations were approximately 25 mg/l and above that reported to abolish pain. In 13 dogs, subendocardial ultrasonic crystal transducers and a high-fidelity pressure transducer were implanted into the LV. Measurements were obtained with and without prior treatment with propranolol to produce beta-adrenergic blockade. LV contractility was assessed by ejection fraction and the end-systolic pressure-volume relationship. The effect of NP on ventricular myocardium was also examined in an in vitro canine right trabecular preparation to compare in vivo and in vitro effects. In the in vivo study, the results showed no decrease in LV contractility during anesthesia regardless of whether propranolol was administered. The in vitro preparation showed only a minimal decrease in isometric tension at the concentrations used in the in vivo study. We conclude that NP anesthesia does not depress LV contractility when concentrations are maintained at approximately 25 mg/l.

How is maximal expiratory flow reduced in canine postpneumonectomy lung growth?

Six dogs underwent left pneumonectomy (P) at 10 wk of age, while four littermates had a sham operation (C). All dogs were studied at 26 wk of age. Pressure capsules were placed on the right lung to measure lobar alveolar pressures and flows, and a Pitot-static tube was used to measure dynamic intrabronchial pressures. Vital capacity and lung elastic recoil did not differ between P and C. At all lung volumes studied, maximum expiratory flows (Vmax) in P were substantially lower than in C. Choke points in P were located more peripherally than in C. In central airways subjected to the same distending pressure, calculated cross-sectional area was significantly lower in P than in C, indicating different bronchial area-pressure behavior. In P, frictional resistances of the right lower, middle, and cardiac lobes were significantly higher than those in C. These results indicate that the reduction in Vmax in P was greater than would have been expected on the basis of reductions in central airway diameter alone. We calculated that, in the middle vital capacity range, approximately 60% of the decrease in Vmax was due to changes in dynamic central airways properties, and approximately 40% was due to increased lobar frictional resistance related to compensatory growth.

Heterogeneity of maximal lobar emptying rates in dogs with compensatory lung growth.

Five dogs underwent left pneumonectomy at 10 wk of age, whereas four littermates underwent a sham operation. At 26 wk of age the postpneumonectomy dogs had total lung vital capacity (VC) and lung weight similar to controls, but maximum expiratory flow was reduced. Pressure capsules were glued to right lower (RLL) and right cardiac (RCL) lobes, and alveolar pressures (PA) were measured during forced expiration. In postpneumonectomy dogs RLL and RCL both emptied more slowly than in control dogs, and emptying was especially delayed in RCL, which underwent the most growth. When both lobes deflated together, PA in RCL and RLL were similar in control dogs, but in postpneumonectomy dogs PA in RCL exceeded that in RLL by approximately 3 cmH2O from 80 to 20% VC. Because the higher driving pressure in RCL compensated for the relatively high resistance of RCL, the pattern of lobar emptying was relatively uniform over these lung volumes. This result was compatible with interdependence of lobar maximum expiratory flows. In addition, at PA of 6-10 cmH2O in postpneumonectomy dogs, maximum emptying rates of RCL were less when RCL deflated alone than when RCL and RLL emptied together, again demonstrating interdependence of lobar maximum expiratory flow.

Aminophylline has little positive inotropic effect and a slightly negative diastolic effect on the left ventricle during hypoxic conditions in dogs.

We examined the effect of aminophylline on left ventricular (LV) mechanics and central hemodynamics under normoxic and hypoxic conditions in respective groups of dogs. In an open-chest preparation, LV end-systolic and diastolic dimensions were measured with ultrasonic crystal transducers seated subendocardially along the anterior to posterior and apex to base axes. In the group studied during hypoxia, measurements were obtained during 3 conditions: normoxia; hypoxia to a PO2 of 30 mm Hg; and during hypoxia when aminophylline was infused to a blood level of about 15 mg/L. In the group studied under normoxic conditions, measurements were initially obtained during normoxia after which aminophylline was also infused to a blood level of 15 mg/L. Intravascular volume was given or removed to maintain LV filling pressures at about 10 mm Hg during all conditions. In the normoxic group, aminophylline caused an increase in stroke volume (SV) and had a positive inotropic effect on the LV. End-systolic dimensions were reduced, while end-diastolic dimensions did not change with aminophylline. On the other hand, under hypoxic conditions, aminophylline did not have a positive inotropic effect: SV did not increase and end-systolic dimensions remained unchanged. Under hypoxic conditions, moreover, aminophylline caused a slight decrease in end-diastolic dimensions by augmenting hypoxia-induced increases in myocardial resting tension. Our results indicate that unlike normoxic conditions, aminophylline may have little beneficial effect on LV performance during hypoxic conditions.

Expiratory flow limitation in dogs with regional changes in lung mechanical properties.

We examined maximum expiratory flow (Vmax) in two canine preparations in which regional changes in lung mechanical properties were produced. In one experiment serial bronchial obstructions were made to determine whether flow-limiting sites (choke points, CP) would occur in series. With the right lung tied off, constrictions were placed at the left lower lobar bronchus (LLL) and left main-stem bronchus. On deflation from total lung capacity, the obstructed LLL and nonobstructed left upper lobe (LUL) emptied into the obstructed left main-stem bronchus. Although a CP common to both lobes was identified at the main-stem obstruction, which limited total Vmax, we questioned whether there was also a CP at the lobar obstruction that fixed LLL flow. In that case the rate of LLL emptying would not be dependent on the presence of the common (i.e., central) CP and thus the flow contribution of the LUL. We found that when the LUL was removed, the LLL increased its rate of emptying. Thus a lobar CP did not fix LLL flow and CP did not occur in series. In a second experiment emphysema was produced in the left lung to reduce lung recoil, whereas the right lung was normal. CP were identified at approximately lobar bronchi of each lung, and the lungs were emptied at different rates. A CP common to both lungs was not identified. Our results indicate that in localized lung disease, if flows from the different regions are high enough, then wave speed is reached in proximal airways, and a CP occurs centrally rather than peripherally. On the other hand, if flows are low, then wave speed is reached peripherally and a CP common to all lung regions does not occur.

Density dependence of maximal flow is lung volume dependent during bronchoconstriction.

We examined the changes in maximum expiratory flow (Vmax) and the density dependence of maximum expiratory flow (delta Vmax) during histamine-induced bronchoconstriction in dogs. Histamine acid phosphate solution was nebulized into the airways of six dogs to produce predominantly peripheral airway obstruction. Vmax air, Vmax with the dogs breathing 80% He-20% O2 (delta Vmax), and airway sites of flow limitation (choke points) were examined at four lung volumes (VL), which ranged from 51 to 23% of the control vital capacity (VC). The findings were interpreted in terms of the wave-speed theory of flow limitation. At all VL, Vmax air decreased during bronchoconstriction by approximately 30% compared with the control value. Resistances peripheral to a 0.3-cm-diam airway were increased about threefold with histamine, whereas resistances between 0.6-cm-diam bronchi and main-stem bronchi increased just slightly. Airway diameters were measured in the air-dried lung at 20 cmH2O transpulmonary pressure. Our results showed that only at 44% VC did delta Vmax decrease in all experiments after histamine to indicate peripheral obstruction (mean: 68.5 to 45%). At 23% VC, delta Vmax increased slightly, from 22 to 28%. At 23 and 36% VC, substantial differences in the wave-speed variables between air and HeO2 were present before bronchoconstriction, so that delta Vmax was low in some dogs, although peripheral airway obstruction was not evident. When bronchoconstriction was produced, delta Vmax at 23% VC could not be decreased further and even increased in four of six dogs. Thus changes in delta Vmax at given lung volume may not reflect the predominant site of airflow obstruction during bronchoconstriction.

Mechanism of reduced maximum expiratory flow in dogs with compensatory lung growth.

We examined the mechanism of the reduced maximum expiratory flow rates (Vmax) in a dog model of postpneumonectomy compensatory lung growth. During forced expiration, a Pitot-static tube was used to locate the airway site of flow limitation, or choke point, and to measure dynamic intrabronchial pressures. The factors determining Vmax were calculated and the results analyzed in terms of the wave-speed theory of flow limitation. Measurements were made at multiple lung volumes and during ventilation both with air and with HeO2. Five of the puppies had undergone a left pneumonectomy at 10 wk of age, and 5 littermate controls had undergone a sham operation. All dogs were studied at 26 wk of age, at which time compensatory lung growth had occurred in the postpneumonectomy group. Vmax was markedly decreased in the postpneumonectomy group compared with control, averaging 42% of the control flow rates from 58 to 35% of the vital capacity (VC). At 23% of the VC, Vmax was 15% less than control. Choke points were more peripheral in the postpneumonectomy dogs compared with controls at all volumes. The total airway pressure was the same at the choke-point airway in the postpneumonectomy dogs as that in the same airway in the control dogs, suggesting that the airways of the postpneumonectomy dogs displayed different bronchial area-pressure behavior from the control dogs. Despite the decreased Vmax on both air and HeO2, the density dependence of flow was high in the postpneumonectomy dogs and the same as controls at all lung volumes examined.