The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence.

OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block. SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 × 10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02). CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Proposal for a new definition of congenital complete atrioventricular block.

The classic old definition of congenital heart block by Yater (1929) is still generally accepted: 'Heart block established in a young patient. There must be some evidence of the existence of the slow pulse at a fairly early age and absence of a history of any infection which might cause the condition after birth: notably diphtheria, rheumatic fever, chorea and congenital syphilis'. However, other definitions are used. We systematically reviewed 1825 cases from 38 separate studies. We conclude that complete AV blocks detected in utero in the absence of structural abnormalities differ from blocks detected later in life with respect to pathogenesis (they are generally associated with maternal anti-Ro/SSA antibodies), poorer childhood prognosis, increased risk of developing late-onset dilated cardiomyopathy, different maternal clinical features and increased risk of recurrence in future pregnancies. For these reasons we propose a new modern definition of congenital complete AV block which might be acceptable to cardiologists, rheumatologists, pediatricians and obstetricians: 'an AV block is defined as congenital if it is diagnosed in utero, at birth or within the neonatal period (0-27 days after birth)'.

Supplementary oxygen and risk of childhood lymphatic leukaemia.

AIM: Childhood leukaemia has been linked to several factors, such as asphyxia and birthweight, which in turn are related to newborn resuscitation. Based on the findings from a previous study a population-based case-control study was performed to investigate the association between childhood leukaemia and exposure to supplementary oxygen and other birth-related factors. METHODS: Children born in Sweden and diagnosed with lymphatic leukaemia between 1973 and 1989 (578 cases) were individually matched by gender and date of birth to a randomly selected control. Children with Down's syndrome were excluded. Exposure data were blindly gathered from antenatal, obstetric and other standardized medical records. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by conditional logistic regression. RESULTS: Resuscitation with 100% oxygen with a facemask and bag immediately postpartum was significantly associated with an increased risk of childhood lymphatic leukaemia (OR = 2.57, 95% Cl 1.21-6.82). The oxygen-related risk further increased if the manual ventilation lasted for 3 min or more (OR = 3.54, 95% CI 1.16-10.80). Low Apgar scores at 1 and 5 min were associated with a non-significantly increased risk of lymphatic leukaemia. There were no associations between lymphatic leukaemia and supplementary oxygen later in the neonatal period or other birth-related factors. CONCLUSION: Resuscitation with 100% oxygen immediately postpartum is associated with childhood lymphatic leukaemia, but further studies are warranted to confirm the findings.

The outcome of children born with pulmonary atresia and intact ventricular septum in Sweden from 1980 to 1999.

OBJECTIVE: To study the outcome of all children born with pulmonary atresia and intact ventricular septum in Sweden between 1980 and 1999. DESIGN: Retrospective study of medical records with review of the initial, preoperative angiocardiographic and echocardiographic examinations. RESULTS: A total of 84 children were born with pulmonary atresia and intact ventricular septum, giving an incidence of 4.2 per 100,000 live births. In all, 77 were operated on with a 1-year survival rate of 75%. Thirty-six children had ventriculocoronary communications, with a 1-year survival rate of 50%. At the end of the study period, 52 children were alive, 32 with biventricular repair, and 19 with univentricular repair. Follow-up time was 14 days-20 years (median, 6 years). Statistical analysis of incremental risk factors for death showed statistical significance for low birth weight, male sex, muscular pulmonary atresia, and having a systemic-to-pulmonary shunt as the sole initial intervention. CONCLUSION: Complete national data of all patients born with pulmonary atresia and intact ventricular septum during 1980-1999 in Sweden revealed a total mortality in accordance with previous reports for results for surgery. Further improvements demand a thorough preoperative investigation of the cardiac anatomy, particularly of the ventriculocoronary communications, to enable right ventricular decompression whenever possible.

Effects of the inspiratory pressure waveform during patient-triggered ventilation on pulmonary stretch receptor and phrenic nerve activity in cats.

OBJECTIVE: To examine the effects of square wave, sinusoidal, and linear inspiratory pressure waveforms during pressure-controlled assist/control ventilation on the firing pattern of pulmonary stretch receptors and phrenic nerve activity. DESIGN: Experimental, comparative study. SETTING: Research laboratory at a university biomedical center. SUBJECTS: Nine anesthetized, endotracheally intubated young cats (2.5-3.4 kg). INTERVENTION: With interposed periods of continuous positive airway pressure (0.2 kPa), each cat was exposed to periods of assist/control ventilation with three different pressure waveforms, where the peak inspiratory pressure (0.74 +/- 0.13 kPa), end-expiratory pressure (0.2 +/- 0.02 kPa), and tidal volume (14.9 +/- 5.22 mL/kg) were kept constant. Preset controlled ventilator rate was set below the rate of spontaneous breathing, and the mechanical inflation time equaled the inspiratory time during spontaneous breathing on continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS: Respiratory rate and arterial blood gases did not change between the three pressure waveforms during assist/control ventilation. Peak pulmonary stretch receptor activity was lower and mean phrenic nerve activity higher during continuous positive airway pressure than during assist/control ventilation (p <.05). Peak inspiratory pulmonary stretch receptor activity was the same with all three pressure waveforms (82 +/- 17 impulses.sec-1) but occurred earlier with square wave than with sinusoidal or linear pressure waveforms (p <.05). The total number of impulses in the phrenic nerve activity burst was smaller with square wave than with the other two pressure waveforms (0.21 +/- 0.17 vs. 0.33 +/- 0.27 and 0.42 +/- 0.30 arbitrary units; p <.05), and the phrenic nerve activity burst duration was shorter with square wave (1.10 +/- 0.45 vs. 1.54 +/- 0.36 and 1.64 +/- 0.25 secs; p <.05). CONCLUSION: Square wave pressure waveform during pressure-controlled assist/control ventilation strongly inhibits spontaneous inspiratory activity in cats. One mechanism for this inhibition is earlier and sustained peak pulmonary stretch receptor activity during inspiration. These findings show that differences in inspiratory pressure waveforms influence the spontaneous breathing effort during assist/control ventilation in cats.

Assisted mechanical ventilation using combined elastic and resistive unloading in cats with severe respiratory failure: effects on gas exchange and phrenic nerve activity.

This study tests the efficacy of respiratory mechanical unloading as a mode of assisted mechanical ventilation in cats with an intact breathing-control system but severe pulmonary parenchymal injury. Twelve anaesthetized, intubated cats received multiple saline lung lavages so that their total respiratory system compliance decreased from 56.1+/-10.4 to 26.8+/-6.8 ml/kPa (p < 0.001) and their PaO2 fell to 12.38+/-4.71 kPa when 100% O2 was used as inspired gas. They were then exposed to three consecutive 15-min periods of CPAP of 0.5 kPa, respiratory unloading and again CPAP of 0.5 kPa. Unloading was applied with end-expiratory pressure of 0.5 kPa, elastic assistance of 0.03 kPa/ml and resistance compensation of 2.0 kPa/l/s. Arterial blood gases for the CPAP baselines did not differ significantly before and after unloading: pH 7.14+/-0.04 vs. 7.16+/-0.06; PaCO2 8.99+/-2.07 vs. 8.33+/-2.01 kPa; PaO2 12.4+/-4.7 vs. 13.3+/-7.6 kPa. Nor did the baselines differ in terms of tidal volume, respiratory rate and phrenic nerve activity. Unloading increased tidal volume substantially by about 50% and increased respiratory rate slightly, while inspiratory time remained unchanged. PaCO2 fell to 6.63+/-1.57 kPa and pH rose to 7.25+/-0.06. Phrenic nerve activity was significantly down-regulated in terms of total number of impulses and mean impulse frequency in the phrenic nerve burst. These results suggest that combined elastic and resistive unloading may be an effective means of assisted mechanical ventilation in severe respiratory failure of pulmonary parenchymal origin.

Short-term outcome of perinatal care in a Swedish county. Mortality, neonatal intensive care and overall evaluation of neuromotor function at 0-10 months of corrected age in preterm and term infants.

Improvements in obstetrical and neonatal care during the last decades have led to a marked increase in survival rate of preterm and term infants. In order to study the short- and long-term outcome in infants who survived neonatal intensive care (NIC) and were born in the county of Uppsala between January 1st 1986 and April 30th 1989, a prospective long-term follow-up study was conducted. Epidemiological data on all infants born in the county during the study period and the short-term outcome, measured as overall neuromotor function at term and at 2, 4, 6 and 10 months of corrected age in 245 infants surviving NIC and 72 healthy control infants are presented. The infants' neuromotor function was evaluated with different clinical neurological methods. In the study population of NIC infants 85.9% survived the neonatal period. The early infant mortality was high in this group 11.6% compared to that of all infants born in the county of Uppsala (0.30%). Only a minority of the infants showed abnormal neuromotor function. A comparison of the results of the overall evaluation of neuromotor function at 10 months of age with those of the examinations made at an earlier age showed poor correspondence in individual infants, especially in preterm and very preterm infants.

Myocardial function after autologous bone marrow transplantation in children: a prospective long-term study.

Early cardiac complications after autologous bone marrow transplantation (ABMT) were recorded for 49 children with haematological malignancies. There was no procedure-related mortality and only two cases of early post-transplant cardiac complications of clinical relevance, both of which were reversible. For 35 long-time survivors (median follow-up 7 y) serial evaluations before and after ABMT included ECG, chest radiography, echocardiography and equilibrium radionuclide ventriculography (RVG). One patient had frequent supraventricular ectopic beats after ABMT, a finding not previously noted. The mean left ventricular diastolic diameter (LVDD) was 104% of expected before ABMT (95% confidence interval 99-110). During the first year post-transplant LVDD was about 110% of expected, but thereafter normalization occurred. The mean shortening fraction before ABMT was 31% (CI 29-34), compared with the mean value of 34% for healthy children in our laboratory, and it ranged between 29% and 33% during the follow-up period. Mean left ventricular ejection fraction determined by RVG was 65% (CI 61-69) and mean right ventricular ejection fraction was 46% (CI 43-49) before ABMT, and they did not change during follow-up. It is encouraging that these heavily pre-treated children could be autografted without serious cardiac complications or deterioration in myocardial performance in a 5-10-y prospect, but longer follow-up is needed for a final evaluation.

Lung hyaluronan and water content in preterm and term rabbit pups exposed to oxygen or air.

Rabbit pups were delivered by cesarean section 1 or 2 d before term, or vaginally around term, and then reared in room air or exposed to intermittent or continuous hyperoxia (> 85%) for up to 9 d. Pups were killed at different ages, and lung hyaluronan (HA; microgram/g of dry lung weight) and lung water content, measured as wet/dry lung weight, were determined. Compared with the day of birth, the lung HA concentration did not change significantly on succeeding days in pups kept in air delivered 2 d (-2 d) or 1 d (-1 d) before term, whereas the water content decreased significantly. Continuous exposure to hyperoxia resulted in a significantly raised lung HA concentration 6 d postterm in both -2 d and -1 d pups, and intermittent exposure to hyperoxia resulted in a significantly raised HA concentration 6 d postterm in -1 d pups, compared with the groups exposed to room air. These increases were accompanied by significantly elevated wet/dry lung weight ratios. Microscopic examination revealed significantly increased HA staining scores in alveoli, arterioles, and bronchioli in both hyperoxia-exposed groups of -2 d pups 6 d postterm, and nonsignificantly higher scores in -1 d and vaginally delivered pups of comparable age, compared with the scores at birth. The results indicate that oxygen exposure neonatally may result in an increase in lung HA accompanied by an increase in lung water content. The increase in lung HA concentration in our study may be an effect of oxygen free radicals or of oxygen-induced stimulation of inflammatory mediators.

Natural history of congenital complete atrioventricular block.

An update of studies on the natural history of congenital complete AV block is presented. A risk for heart failure, syncope, and sudden death is present at any age including fetal life. Unfavorable prognostic signs in utero are low and decreasing ventricular rate (VR), hydrops, AV valve regurgitation, and low aortic flow velocity. Indications for pacing in infancy are congestive heart failure, ventricular rate < 55 beats/min in isolated block and < 65 beats/min with associated disease, prolonged OTc, syncope attacks, frequent ventricular ectopic beats, and alternating ventricular pacemakers. Indications for immediate pacing in childhood and adult life are syncope, presyncope, VR rates lower than median for age, periods of junctional exit block, prolongation of QTc and mitral regurgitation, and change of ventricular pacemaker. Pacing is recommended to all patients older than 15 years.

Trigger delay in infant ventilators.

In an experimental study we determined the response trigger delay time of three infant ventilators with a capacity to detect and support spontaneous breathing. We measured this in anaesthetized cats as the time between the start of phrenic nerve activity and the increase in airway pressure caused by the subsequent inflation. Two modes of ventilatory support were used, namely Assist/Control (A/C) and synchronised intermittent mandatory ventilation (SIMV). We found that ventilators equipped with flow sensors close to the free end of the endotracheal tube had a shorter trigger delay than a ventilator which detected breathing with an abdominal sensor. Further, the trigger delay was shorter in SIMV mode than in A/C mode of operation. A higher set sensitivity reduced the response time. We conclude that triggered ventilation may be used in infants, at least when the spontaneous breathing rate is below 60 breaths per minute. This mode of ventilation could be useful when infants are to be weaned off the ventilator.

Effects of ventilator resistance and compliance on phrenic nerve activity in spontaneously breathing cats.

This study investigates the effects of respiratory mechanical loading and unloading on phrenic nerve activity and ventilation. Ten adult cats were anesthetized, intubated, and connected to a servocontrolled infant ventilator while breathing spontaneously in continuous positive airway pressure mode. The ventilator was then set to decrease the pressure at the airway opening in proportion to the inspiratory airflow or the volume of spontaneous breathing (resistive or elastic loading) or to increase the pressure at the airway opening accordingly (resistive or elastic unloading, also called proportional assist ventilation). When compared with continuous positive airway pressure, both resistive and elastic loading increased the number of phrenic nerve impulses per breath and the mean frequency of impulses (p < 0.01, ANOVA). In contrast, elastic unloading decreased phrenic nerve activity significantly in normal and injured lungs. Resistive unloading in normal lungs did not change phrenic nerve activity significantly. The compensatory response in phrenic nerve activity was not large enough to completely offset effects of loading and unloading on ventilation: elastic and resistive loading decreased ventilation. Unloading had the opposite effect on ventilation, particularly in injured lungs. We conclude that respiratory mechanical loading and unloading have statistically significant, opposite effects on phrenic nerve activity and opposite effects on ventilation.

Isolated congenital complete atrioventricular block in adult life. A prospective study.

BACKGROUND: The prognosis of congenital complete atrioventricular block (CCHB) is usually considered favorable in adults. This belief is based on studies comprising a limited number of patients and with rather short observation times. In the present study, the natural history of the disease was investigated by a prospective follow-up through decades of adult life of patients with a large group having well-defined CCHB without structural heart disease. METHODS AND RESULTS: The diagnostic criteria of CCHB proposed by Yater were applied. Patients registered as having CCHB in 1964, supplemented by younger patients all without symptoms during their first 15 years of life, were selected. The study was limited to patients with isolated, complete, permanent block. An interview was conducted with all patients and clinical follow-up data obtained. There were finally 102 patients, 61 women and 41 men. In November 1994, the time of observation, after the age of 15 years in survivors, was between 7 and 30 years. The mean age at follow-up or at death was 38 years, median age 37 years, and range 16 to 66 years. Stokes-Adams (SA) attacks occurred in 27 patients, in 8 with a fatal outcome. The first attack was fatal in 6 of these 8 patients. Nineteen survived and a pacemaker (PM) was implanted thereafter. Another 8 patients received a PM because of repeated fainting spells, and 27 others have had a PM implanted for other reasons such as fatigue, effort dyspnea, dizziness, ectopies during exercise tests, mitral regurgitation, and a low ventricular rate (VR). VR decreased with age, with a mean rate at 15 years of 46 beats per minute (bpm), at 16 to 20 years of 43 bpm, at 21 to 30 years of 41 bpm, at 31 to 40 years of 40 bpm, and after 40 years of age of 39 bpm. SA attacks occurred in all 7 patients with prolonged QTc time. Low VR at rest or at work, presence of bundle-branch block pattern, low working capacity, and ectopies at rest and/or during effort were not statistically significant risk factors. SA attacks occurred in 6 patients without any of these signs. Mitral regurgitation developed in 16 patients and 4 died. A PM reduced the risk of death. A change to a lower degree of block occurred in 6 patients. CONCLUSIONS: Prophylactic PM treatment is recommended even for symptom-free adults with CCHB because of the high incidence of unpredictable SA attacks with considerable mortality from first attacks, a gradually decreasing VR, significant morbidity, and a high incidence of "acquired" mitral insufficiency.

Assisted mechanical ventilation using elastic unloading: a study in cats with normal and injured lungs.

Elastic unloading [otherwise known as negative ventilator compliance (Cv) or proportional assist ventilation] is a new mode of assisted mechanical ventilation. The ventilator continuously measures the volume of spontaneous breathing (V) and adjusts the pressure at the airway opening in proportion to V. The quotient of pressure above the baseline end-expiratory level per unit of V (the gain of the assist) is constant at any point in time and can be preset. The apparatus used for this study can also generate elastic loading (positive Cv) by decreasing the pressure at the airway opening in proportion to V. This might be useful during the weaning process. This study compares measured values of total compliance of the combined lung-respirator system (Ctot) with values predicted according to theory, where 1/Ctot = 1/Cv + 1/Cl with Cl being the lung compliance. Respiratory mechanical data were derived from esophageal pressure and airflow in eight anesthetized, intubated, spontaneously breathing cats. Different Cv levels were set on the ventilator both before and after lung injury with xanthine oxidase. The difference (mean +/- SD) between the measured and predicted Ctot was 1.4 +/- 21.4% (healthy lungs) and -11.6 +/- 14.1% (injured lungs) during unloading and 2.5 +/- 7.5% (healthy lungs) during elastic loading. An elevation of Ctot decreased the expiratory airflow. Tidal volume increased slightly in healthy lungs and arterial PCO2 decreased. We conclude that the effects of Cv on the total compliance of the combined lung-respirator system can accurately be predicted.

Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.

Airway pressures during positive pressure ventilation with superimposed oscillations before and after lung injury in the cat.

This study was made to determine how oscillations superimposed on intermittent positive pressure ventilation (IPPV) influence the arterial blood gases, pH and the airway pressures during adequate alveolar ventilation i.e. at inhibition of inspiratory activity, before and after experimentally induced lung injury in the anaesthetized cat. Two IPPV frequencies were studied. The lung was injured by instillation of xanthine oxidase into the upper airways during IPPV. The peak, mean and end-expiratory intrapleural and airway (intratracheal) pressures at two levels were measured and the arterial blood gases and pH were determined at inhibition of inspiratory activity with and without superimposition of oscillations on the ventilatory pattern. Before lung injury, superimposed oscillations lowered the airway pressures only at an IPPV rate of 15 breaths per minute (b.p.m.). After lung injury, such oscillations increased the airway pressures only at 15 b.p.m. The airway pressures were always lower at 60 than at 15 b.p.m.

Afferent activity in pulmonary stretch receptors before and after lung injury.

This study was undertaken to determine the effect of a lung-injury on the activity of slowly adapting pulmonary stretch receptors. Comparisons of receptor activity were made at inhibition of inspiratory (phrenic nerve) activity. The inspiratory activity of these receptors was found to be decreased after lung-injury.

Intravenous injection of hypertonic NaCl solution stimulates pulmonary C-fibers in dogs.

Intravenous injection of hypertonic NaCl solution evokes reflex bradycardia and hypotension, effects thought to result from stimulation of afferent vagal endings in the lungs. To identify the afferents responsible for these effects, we recorded vagal impulses arising from endings in the lungs and lower airways of anesthetized dogs and examined the response to injection of hypertonic solutions into the pulmonary circulation. Injection of 4,800 mmol/l NaCl solution (1 ml/kg) stimulated 39 of 49 pulmonary C-fibers, their impulse frequency increasing 35-fold. Stimulation was concentration dependent, the minimum effective concentration being between 1,200 and 4,800 mmol/l. Rapidly adapting receptors were also stimulated in a concentration-dependent manner, 35 of 41 receptors being stimulated by 4,800 mmol/l NaCl solution, firing increasing fivefold. Bronchial C-fibers were not stimulated by injection into the pulmonary circulation but were by injection into the bronchial artery. Hypertonic urea solutions had qualitatively similar but smaller effects on pulmonary C-fibers and rapidly adapting receptors. The results suggest that the reflex effects of intravenous injection of hypertonic solutions result principally from stimulation of pulmonary C-fibers.