Clinical predictors and microbiology of ventilator-associated pneumonia in the intensive care unit: a retrospective analysis in six Italian hospitals.

The purpose of this study was to assess the main clinical predictors and microbiological features of ventilator-associated pneumonia (VAP) in the Intensive Care Unit (ICU) environment. This work is a retrospective analysis over one year from September 2010 to September 2011. Patients' risk factors, causes of admission, comorbidities and respiratory specimens collected in six Italian ICUs were reviewed. Incidence and case fatality rate of VAP were evaluated. After stratification for VAP development, univariate and multivariate analyses were performed to assess the impact of patients' conditions on the onset of this infection. A total of 1,647 ICU patients (pts) were considered. Overall, 115 patients (6.9 %) experienced at least one episode of VAP. The incidence rate for VAP was 5.82/1,000 pts-days, with a case fatality rate of 44.3 %. Multivariate analysis showed that admission for neurological disorders (aIRR 4.12, CI 1.24-13.68, p = 0.02) and emergency referral to ICU from other hospitals (aIRR 2.11, CI 1.03-4.31, p = 0.04) were associated with higher risk of VAP, whereas a tendency to a higher risk of infection was detected for admission due to respiratory disease, cardiac disease, trauma and for having obesity or renal failure. A total of 372 microbiological isolates from respiratory specimens were collected in VAP patients. The most common species were Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, showing high resistance rates to carbapenems. Neurological disorders and emergency referral at the admission into the ICU are significantly associated with the onset of VAP. A high incidence of multi-drug resistant Gram- species was detected in the respiratory specimens.

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients.

BACKGROUND: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. METHODS: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 µg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. RESULTS: A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). CONCLUSION: Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. METHODS: Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 microg m(-2) once every 3 weeks. The primary aim of the study was progression-free survival (PFS). RESULTS: No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months. CONCLUSION: NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.

Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours.

BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development.

In vivo administration of GM-CSF promotes the clearance of apoptotic cells: effects on monocytes and polymorphonuclear leukocytes.

The clearance of apoptotic cells is crucial to avoid chronic inflammation and autoimmunity. Little is known about the factors that regulate it in vivo. We show that granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to carcinoma patients confers to their leukocytes a significantly higher ability to phagocytose apoptotic cells than before (P < 0.005). GM-CSF increased the concentration of monocytes and polymorphonuclear leukocytes in the peripheral blood and activated circulating polymorphonuclear leukocytes. Both effects abated early after treatment, whereas phagocytosis of apoptotic cells was still significantly higher after 18 days compared with basal values (P < 0.005 and P < 0.025 for monocytes and polymorphonuclear leukocytes, respectively). On in vitro phagocytosis of apoptotic cells monocytes, but not polymorphonuclear leukocytes, up-regulated MHC class II membrane expression. These findings are consistent with the possibility that GM-CSF endows both scavenger and antigen-presenting leukocytes with the ability to internalize apoptotic tumor cells.

Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Increased interleukin-10 serum levels in patients with solid tumours.

In 40 out of 99 patients (40.4%) with solid tumours of different tissue, but the same stage (IV), elevated serum levels of interleukin-10 were observed. The mean levels of the cytokine in patients with malignant melanoma (24.3 ng/ml), pancreatic (6.8 ng/ml) or gastric (6.3 ng/ml) adenocarcinoma were significantly higher than in healthy subjects (3.4 ng/ml) or in patients with uterine fibroma (1.7 ng/ml). Patients with colon (6.8 ng/ml) and renal (5.7 ng/ml) carcinoma had similar values of interleukin-10 but did not significantly differ from controls. Interleukin-10 is known to suppress the functions of both T lymphocytes and macrophages, working as a general dampener of the immune and inflammatory responses. The observation of increased circulating levels of interleukin-10 in cancer patients may have important implications for future investigations, immunological monitoring and therapeutic intervention on neoplastic patients, and suggests a mechanism for tumour cells escaping from immune surveillance.

The feasibility of repetitive courses of high-dose continuous intravenous infusion interleukin-2 and subcutaneous alpha-interferon with polychemotherapy in advanced malignant melanoma.

AIMS AND BACKGROUND: A Phase I study of repetitive courses of chemotherapy (carmustine, cis-platinum, dacarbazine) and immunotherapy (continuous intravenous infusion recombinant interleukin-2 (rIL-2) and subcutaneous (sc) alpha-interferon 2b) plus tamoxifen was performed in order to establish a more efficacious way to sequence this kind of treatment for advanced malignant melanoma. STUDY DESIGN: Patients who had measurable metastatic melanoma, a Karnofsky performance status > or = 80, and no clinically significant hematologic or cardiac disfunction were considered eligible. Treatment consisted of BCNU, 150 mg/m2 i.v. day 1 in alternating cycles; DTIC, 220 mg/m2 i.v. days 1, 2 and 3; CDDP, 25 mg/m2 i.v. days 1, 2 and 3; tamoxifen 10 mg twice/day per os continuously; rIL-2, 18 x 10(6) IU/m2/day continuous i.v. infusion days 5-8 (96 h) and days 19-22 (96 h); alpha-interferon (IFN) s.c. 3 x 10(6) U day 12, 6 x 10(6) U day 14, 9 x 10(6) U days 16, 19, 21, 23, 26, and 28 (from cycle 2, 9 x 10(6) U days 2, 5, 7, 9, 12, 14, 16, 19, 21, 23, 26, and 28). Two consecutive cycles were planned until response evaluation. RESULTS: Three patients were treated according with the protocol; none of them was able to respect the planned dose-intensity schedule. The given dose intensity/planned dose intensity ratios were as follows: DTIC, 0.74 (range, 0.70-0.80); CDDP, 0.77 (0.72-0.80); BCNU, 0.77 (0.72-0.80); rIL-2, 0.65 (0.36-0.80); alpha-IFN, 0.01 (0-0.03); tamoxifen, 1.0. Systemic side effects of rIL-2 and myelotoxicity were the main reasons for treatment delay and/or dose-reduction, and for the long period of hospital care. CONCLUSIONS: We conclude that the treatment schedule is not feasible. However, since we believe that combined chemo-immunotherapy is a potentially active treatment in metastatic malignant melanoma, we have modified it in order to make it more feasible and consequently efficacious.

Intrapleural administration of interleukin-2 and LAK cells in locally advanced non-small-cell lung cancer. A case report.

AIMS AND BACKGROUND: The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. STUDY DESIGN: We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 N0 M0-stage IIIb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3-9 x 10(9)/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rIL-2 (1.8-7.2 x 10(6) IU/day), for 5 days. RESULTS: We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 x 10(9)/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. CONCLUSIONS: This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial.

BACKGROUND: The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rlL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 10(6) lU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-alpha at a daily dose of 6 x 10(6) IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. RESULTS: Twenty-three percent (95% CI:+/-17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI:+/-11.9) and 9% (95% CI:+/-11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. CONCLUSIONS: Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

Discontinuity between inspiratory and postinspiratory diaphragm activity in man and rabbit.

Diaphragm activity (Edi, 20 Hz low cutoff) was recorded with great time resolution to ascertain whether there is a discontinuity between its inspiratory and postinspiratory periods in humans. We first determined in anesthetized rabbits that gaps or notches in Edi occurred within 80 msec before and after the end of mechanical inspiration in 70% of the analysable breaths in the esophageal lead and in 77% in direct leads. We then determined from the esophageal lead of 4 conscious subjects that gaps or notches in Edi occurred during the above-defined period in 45% of 682 analysable breaths. In each subject mean of moving average Edi (12 msec averaging interval) was computed out of 14-24 breaths, free of ECG artifacts within 200-250 msec before and after end inspiration. A deep indentation occurred near end-inspiration despite the lack of gaps or notches in 1/2 to 4/5 of these breaths. These results suggest that also in humans postinspiratory diaphragm activity does not represent the decay of inspiratory ramp.

Inspiratory facilitation and inhibition from pulmonary stretch receptors in rabbits.

In anesthetized rabbits firing rate (FR) of single fibers of diaphragm and of parasternal intercostal muscles (PIM) was determined at 30, 50 and 70% of control inspiratory time. During first inspiratory effort after airway occlusion at end expiration it increased on the average by 12.1 +/- 0.6 and 43.0 +/- 2.2% relative to control. Under pulmonary stretch receptor (PSR) block with SO2 this increase disappeared in diaphragm and fell to 28.3 +/- 1.8% in PIM. During first inspiratory efforts under PSR block FR decreased by 11.3 +/- 2.2% in diaphragm and 18.3 +/- 1.6 in PIM relative to unblocked efforts. In open inspirations FR under block did not decrease significantly either in diaphragm or PIM relative to unblocked inspirations. Moving average electromyography of diaphragm and of PIM showed similar trends. These results suggest that PSR discharge at FRC activates a mechanism facilitating inspiratory activity while during inspiration it also activates a mechanism inhibiting this activity since early inspiration. Both effects are greater on PIM.

Relative decay rate of inspiratory muscle pressure and breath timing in man.

The decay rate of inspiratory muscle pressure (PmusI) was measured during the postinspiratory period of zero flow (TEz) occurring under a discontinuous inspiratory elastic load with the following tests, (a) Voluntary changed breathing frequency (f) at similar end-inspiratory muscle pressure (PmuseI), (b) as above plus dead space, hence greater PmuseI, (c) breathing spontaneously through a dead space or during exercise to obtain different f at similar PmuseI. The decay rate of PmusI relative to PmuseI (RDRI) at increased f was similar to the corresponding relative decay rate of transdiaphragmatic pressure. Hence, the increase of f did not elicit phasic activity of expiratory muscles during TEz. RDRI increased proportionally to f: i.e. for a given f, the decay rate of PmusI was proportional to PmuseI. RDRI increased hyperbolically with decrease of expiratory time and was not directly related to inspiratory time. In each subject these relationships were unique for different tests. These findings show that increase of Pmusel alone does not shorten the persistence of PmusI during expiration, whereas a timing factor, by increasing RDRI, allows shortening of expiration without the intervention of expiratory muscles.

Selective activation of quadriceps muscle fibers according to bicycling rate.

Moving average electromyography (MA) of quadriceps muscle bellies has been recorded during bicycling at different rates (30-70 cycles/min) or forces (1-3 kg). For power increments (50-100%) achieved by increasing force at constant rate, MA during pedal downstroke always increased. For similar power increments achieved by increasing the rate at constant force, MA did not increase (37% of cases), increased less (37%), or increased similarly (26%). Investigations by others on the rat suggest that the lack of increase of MA despite power increment was not compensated by other muscle activity; hence it indicates a shift from slow to fast fibers, which provide greater power per unit stimulus. Smaller increase of MA with increasing rate rather than force at isopower could depend on this shift or on muscle properties, if operating on ascending limb of power-velocity curve. This, however, does not seem the case for slow fibers, which should develop peak power at about 25 cycles/min. Hence, fibers of quadriceps muscle of humans seem selectively activated according to movement speed, as previously found in inspiratory muscles of rabbits.

Decay of inspiratory muscle activity and breath timing in man.

Time required by moving average EMG of diaphragm and parasternal intercostal muscle to decay to 25% of its peak (T0.25) decreased of expiratory time (TE). Accordingly, relative decay rate (RDRI) of EMG increased of breathing frequency (f). This confirms conclusions based on decay of inspiratory muscle pressure under discontinuous inspiratory elastic load (DIL). Data were better fitted by power functions: only this combination of T0.25 vs. TE and RDRI vs. f equations provided a relationship fitting corresponding inspiratory time vs. TE data. For each timing, RDRI of EMG was higher under DIL than during unloaded breathing. Under DIL scattering of EMG data increased, coupling between diaphragm and parasternal muscle EMG decreased, and RDRI of EMG was higher than that of pressure, likely because of muscle intrinsic properties. This difference decreased with the increase of f: this could be due to recruitment of fast fibers at high f. Both during loaded and unloaded breathing T0.25 was proportional to time from peak to zero EMG, indicating that decay shape did not change with timing.

Effect of stretching on the elastic characteristics and the contractile component of frog striated muscle.

1. The force-velocity relationship and the stress-strain curve of the so-called series elastic component (s.e.c.) of frog sartorius, semitendinosus and gastrocnemius have been determined during shortening against a given force (isotonic quick-release) and at high speed (controlled release): (a) from a state of isometric contraction and (b) after stretching of the contracted muscle. In both cases the muscle was released from the same length: this was usually slightly greater than the muscle's resting length.2. The muscle released immediately after being stretched is able to shorten against a constant force, P, equal to or even greater than the isometric force, P(0), at the same length. When the force P applied to the muscle is reduced below P(0) the velocity of shortening is greater after stretching, and the force-velocity curve is therefore shifted along the velocity axis: the shift is maximal when P is near to P(0) and it decreases rapidly with decreasing P.3. The extent of shortening of the s.e.c. required to make the force fall from P(0) to zero is 50-100% greater when the muscle is released immediately after stretching than when it is released from a state of isometric contraction. This difference is found by using either the controlled release method or the isotonic quick-release method.4. If a time interval is left between the end of stretching and the onset of shortening of the contracted muscle (controlled release method), the length change of the s.e.c., for a given fall of the force, is reduced and approaches that taking place when the muscle is released from a state of isometric contraction.5. Curare does not affect the results described above, indicating that these do not depend on modification of the neuromuscular transmission.6. It is concluded that stretching a contracted muscle modifies temporarily: (a) its elastic characteristics, as shown by the greater amount of mechanical energy released for a given fall of the force at the muscle's extremities, and (b) its contractile machinery, as it is suggested by the change of the force-velocity relationship.

Reflex partitioning of inputs from stretch receptors of bronchi and thoracic trachea.

A selective block of slowly adapting stretch receptors in anesthetized rabbits was induced by exposing to SO2 all thoracic airways (T) or the carina and bronchi alone (B). Increment of inspiratory time (TI) relative to control was 61% greater under B than T. The reverse would have happened if input responsible for Breuer-Hering inflation reflex originated from both bronchi and trachea. Hence, bronchial input activates inspiratory off-switch, while tracheal input delays its activation. During single inspiratory efforts with airways closed at end expiration diaphragm activity (Adi) decreased and TI0 increased relative to control equally under B and T. Hence, the input facilitating central inspiratory activity at end expiratory volume does not stem from trachea. At end of inspiratory ramp Adi stopped within 43 msec at control and 57 msec under B and T. Hence, bronchial input speeds up off-switching of inspiration. Postinspiratory Adi was greater under B than T, and nearly nil at control. Hence, bronchial input inhibits postinspiratory Adi, while tracheal input facilitates it. Inspiratory and expiratory flows were more damped under B than T, and under T than at control.

Breathing pattern and diaphragm EMG after SO2 in rabbit intra- or extrathoracic airways.

In anesthetized rabbits under SO2 block of slowly adapting stretch receptors (SAR) in intrathoracic airways TI increased by 49.7 +/- 6.9% and VT by 19.5 +/- 3.7%. TE decreased for small increases of TI and vice versa. Slope of moving average of diaphragm EMG (M.A.) decreased by 16.7 +/- 4.1% from 0 to 30% TI control, and increased by 26.3 +/- 8.1% from 30 to 70%. Considering that discharge from intrathoracic SAR increases during inspiration, these changes of M.A. indicate that their input facilitates inspiration at its beginning, but inhibits it later on, in line with previous conclusions based on SAR block which included 2/3 of extrathoracic trachea (ETT). Neither SO2 nor pressures from -40 to +40 cm H2O in ETT changed breathing pattern or M.A.. Hence, SAR of ETT do not affect parameters studied in rabbits. When extrathoracic airways were exposed to SO2 TI increased by 30.5 +/- 8.2%, TE by 37.9 +/- 5.1%, VT did not change. Hence, some receptors rostral to trachea, involved in respiratory control, are affected by SO2.

Effects of stretch receptors of bronchi or trachea on genioglossus muscle activity.

Activity of genioglossus muscle (GG) was recorded in anesthetized rabbits at control and under SO2 block of slowly adapting stretch receptors in thoracic airways (T) or in bronchi alone (B). At control peak activity occurred at 10% of inspiratory time, followed by a slight and a marked decrease. T and, particularly, B delayed onset and slowed rise of GG activity; then, this increased slightly under T and more under B, becoming greater than at control. During inspiratory efforts at end-expiratory volume GG activity at control was equal to that during open inspirations up to its peak, then progressively greater; during inspiratory efforts GG activity under T and B was equally smaller than at control. These findings indicate that bronchial input facilitates GG activity at end-expiratory volume and inhibits it at larger volumes: these effects are greater than those previously detected on diaphragm. Moreover, tracheal input inhibits onset and development of GG activity. Under all conditions end of inspiratory activity was simultaneous in GG and in diaphragm. Time to peak inspiratory flow correlated with time to early peak in GG activity.

Slow to fast shift in inspiratory muscle fibers during heat tachypnea.

The firing patterns of single diaphragm fibers and electromyographic moving average (M.A.) of diaphragm and parasternal intercostal muscles (P.I.) were studied in rabbits during control and heat tachypnea at nearly constant tidal volume (VT). During tachypnea the percentage of single diaphragm fibers with relatively high values of peak firing rate (fp) increased. Conversely, fibers with relatively low values of fp at control (likely slow) showed little or no increase of this parameter during tachypnea. These findings, similar to those previously found in P.I., suggest a slow to fast shift in diaphragm fibers during tachypnea. Inspiratory flow at half VT control increased significantly during tachypnea, while the corresponding M.A. of diaphragm did not change. Moreover, during tachypnea mean inspiratory flow increased significantly, while the mean M.A. over inspiratory time did not change either in diaphragm or in P.I. Since during tachypnea the firing rate of most fibers is greater than at control, a lack of increase of M.A. in spite of an increased mechanical power confirms a shift from slow to fast inspiratory muscle fibers under this condition.