Clinical outcomes of antithrombin III supplementation in an overt disseminated intravascular coagulation: a longitudinal single-institutional experience and retrospective analysis.

BACKGROUND: Antithrombin is a small plasma glycoprotein synthesized in the liver that belongs to the serpin family of serine protease inhibitors and inactivates several enzymes in the coagulation pathway. It plays a leading major factor on coagulation pathway, therefore administration of antithrombin is essential to treat serious clinical conditions such as disseminated intravascular coagulation (DIC). Despite the theoretical benefits of antithrombin supplementation, the optimal antithrombin activity for heparin efficacy and the benefits of antithrombin supplementation in various disease entities are not yet fully understood. METHODS: The strict administration guidelines on antithrombin III in cases of DIC by the National Health Insurance Service and the Ministry of Food and Drug Safety complied as follows: antithrombin levels below 20 mg/dL in adults; antithrombin activity below 70% of normal in adults; total administration period of antithrombin must be carefully limited to within maximum 3 days, and the total administration dose must be below 7,000 international unit (IU), (loading dose, 1,000 IU in 1 hour: maintenance dose, 500 IU every 6 hours for 3 days). RESULTS: We identified 76 eligible for analysis according to the above-mentioned criteria in our institution (male/female, 59/17). Forty-four were identified to the non-survivor group and 32 patients were recognized as the survivor group. The baseline parameters in the non-survivor and survivor groups were comparable with no significant differences in age (66.5±18.1 vs. 66.0±16.2 years, P=0.90), sex (32/12 vs. 27/5, P=0.35), hospital length of stay (31.1±34.5 vs. 31.2±26.1 days, P=0.99), sequential organ failure assessment (SOFA) (7.3±2.5 vs. 6.6±2.0, P=0.22), simplified acute physiology score II (SAPS II) (46.0±8.8 vs. 43.5±9.2, P=0.23), cause for DIC (P=0.95), and underlying disease (P=0.38). The levels of antithrombin III on the day just before the administration significantly lower in the non-survivor groups than in the survivor groups (50.1%±13.6% vs. 57.6%±12.5%, P=0.01). The hemoglobin level in the 2nd day and 7th day after antithrombin III administration was significantly different between the non-survivor and survivor groups (9.9±1.9 vs. 11.0±2.0 g/dL, P=0.01, and 9.4±1.8 vs. 10.5±1.6 g/dL, P=0.006). The antithrombin III levels on the day of administration [area under the curve (AUC) =0.672] demonstrated significantly better prediction of mortality than the A antithrombin III levels on 1st day (AUC =0.552), the 2nd day (AUC =0.624), and 7th day (AUC =0.593). CONCLUSIONS: Our study suggests that the antithrombin administration may be effective tools for DIC treatment, and may be more positively considered, especially in the cases of DIC, which is a frequent complication of septic shock, sepsis, and other critical disease entities and which is associated with a high level of mortality. Furthermore, our study also suggests that the total doses and periods of antithrombin administration, which recommended by national guidelines, may be insufficient, therefore prolongation of period and increase of total dose of antithrombin supplement might be necessary.

Divergent expiratory braking activity of costal and crural diaphragm.

BACKGROUND: There is increasing clinical interest in understanding the contribution of the diaphragm in early expiration, especially during mechanical ventilation. However, current experimental evidence is limited, so essential activity of the diaphragm during expiration and diaphragm segmental differences in expiratory activity, are unknown. OBJECTIVES: To determine if: 1) the diaphragm is normally active into expiration during spontaneous breathing and hypercapnic ventilation, 2) expiratory diaphragmatic activity is distributed equally among the segments of the diaphragm, costal and crural. METHODS: In 30 spontaneously breathing male and female canines, awake without confounding anesthetic, we measured directly both inspiratory and expiratory electrical activity (EMG), and corresponding mechanical shortening, of costal and crural diaphragm, during room air and hypercapnia. RESULTS: During eupnea, costal and crural diaphragm are active into expiration, showing significant and distinct expiratory activity, with crural expiratory activity greater than costal, for both magnitude and duration. This diaphragm segmental difference diverged further during progressive hypercapnic ventilation: crural expiratory activity progressively increased, while costal expiratory activity disappeared. CONCLUSION: The diaphragm is not passive during expiration. During spontaneous breathing, expiratory activity -"braking"- of the diaphragm is expressed routinely, but is not equally distributed. Crural muscle "braking" is greater than costal muscle in magnitude and duration. With increasing ventilation during hypercapnia, expiratory activity -"braking"- diverges notably. Crural expiratory activity greatly increases, while costal expiratory "braking" decreases in magnitude and duration, and disappears. Thus, diaphragm expiratory "braking" action represents an inherent, physiological function of the diaphragm, distinct for each segment, expressing differing neural activation.

Expiratory and inspiratory action of transversus abdominis during eupnea and hypercapnic ventilation.

BACKGROUND: Recently, there is interest in the clinical importance of monitoring abdominal muscles during respiratory failure. The clinical interpretation relies on the assumption that expiration is a passive physiologic process and, since diaphragm and abdomen are arranged in series, any inward motion of the abdominal wall represents a sign of diaphragm dysfunction. However, previous studies suggest transversus abdominis might be active even during eupnea and is preferentially recruited over the other abdominal muscles. OBJECTIVE: 1) Is transversus abdominis normally recruited during eupnea? 2) What is the degree of activation of transversus abdominis during hypercapnia? 3) Does the end-inspiratory length of transversus abdominis change during hypercapnia, while diaphragm function is normal? METHODS: In 30 spontaneously breathing canines, awake without confounding anesthetic, we measured directly both electrical activity and corresponding mechanical length and shortening of transversus abdominis during eupnea and hypercapnia. RESULTS: Transversus abdominis is consistently recruited during eupnea. During hypercapnia, transversus abdominis recruitment is progressive and significant. Throughout hypercapnia, transversus abdominis baseline end-inspiratory length is not constant: baseline length decreases progressively throughout hypercapnia. After expiration, into early inspiration, transversus abdominis shows a consistent neural mechanical post -expiratory expiratory activity (PEEA) at rest, which progressively increases during hypercapnia. CONCLUSION: Transversus abdominis is an obligatory expiratory muscle, reinforcing the fundamental principle expiration is not a passive process. Beyond expiration, during hypercapnic ventilation, transversus abdominis contributes as an "accessory inspiratory muscle" into the early phase of inspiration. Clinical monitoring of abdominal wall motion during respiratory failure may be confounded by action of transversus abdominis.

Parasternal intercostal function during sustained hypoxia.

Ventilatory response to sustained isocapnic hypoxia in adult humans and other mammals is characterized by a biphasic pattern, with attenuation of neuromotor output to the diaphragm. However, there is no a priori reason that hypoxia-mediated attenuation of respiratory drive would be a common event among other respiratory muscles. At present, little is known about the function of the chest wall muscles during sustained hypoxia. As an obligatory inspiratory muscle with potential to act as a surrogate for neural drive to the relatively inaccessible costal diaphragm, parasternal intercostal has gained interest clinically: its function during a sustained hypoxic insult, as may occur in respiratory failure, warrants investigation. Therefore, in 11 chronically instrumented awake canines, we simultaneously recorded muscle length and shortening and electromyogram (EMG) activity of the parasternal chest wall inspiratory muscle, along with breathing pattern, during moderate levels of sustained isocapnic hypoxia lasting 20-25 min (mean 80 ± 2% oximeter oxygen saturation). Phasic inspiratory shortening and EMG activity of the parasternal intercostal were observed throughout room air and hypoxic ventilation in all animals. Temporal changes in parasternal intercostal shortening tracked the biphasic changes in ventilation during sustained hypoxia. Mean shortening and EMG activity of parasternal intercostal muscle increased significantly with initial hypoxia (P < 0.01) and then markedly declined with constant hypoxia (P < 0.05). We conclude that attenuation of central neural respiratory drive extends to the primary chest wall inspiratory muscle, the parasternal intercostal, during sustained hypoxia, thus directly contributing to biphasic changes in ventilation.NEW & NOTEWORTHY With the potential to act as a surrogate for the generally inaccessible costal diaphragm, parasternal intercostal has gained great interest clinically as a muscle to monitor neural drive and function in respiratory disease. This study demonstrates for the first time the impact of sustained hypoxia on neural activation and mechanical contraction of the parasternal intercostals. Parasternal intercostals reveal a biphasic action during the time-dependent hypoxic response, with a transient increase in shortening and EMG activity with acute hypoxia followed by a progressive decline when hypoxia is sustained.

Parasternal intercostal, costal, and crural diaphragm neural activation during hypercapnia.

The parasternal intercostal is an obligatory inspiratory muscle working in coordination with the diaphragm, apparently sharing a common pathway of neural response. This similarity has attracted clinical interest, promoting the parasternal as a noninvasive alternative to the diaphragm, to monitor central neural respiratory output. However, this role may be confounded by the distinct and different functions of the costal and crural diaphragm. Given the anatomic location, parasternal activation may significantly impact the chest wall via both mechanical shortening or as a "fixator" for the chest wall. Either mechanical function of the parasternal may also impact differential function of the costal and crural. The objectives of the present study were, during eupnea and hypercapnia, 1) to compare the intensity of neural activation of the parasternal with the costal and crural diaphragm and 2) to examine parasternal recruitment and changes in mechanical action during progressive hypercapnia, including muscle baseline length and shortening. In 30 spontaneously breathing canines, awake without confounding anesthetic, we directly measured the electrical activity of the parasternal, costal, and crural diaphragm, and the corresponding mechanical shortening of the parasternal, during eupnea and hypercapnia. During eupnea and hypercapnia, the parasternal and costal diaphragm share a similar intensity of neural activation, whereas both differ significantly from crural diaphragm activity. The shortening of the parasternal increases significantly with hypercapnia, without a change in baseline end-expiratory length. In conclusion, the parasternal shares an equivalent intensity of neural activation with the costal, but not crural, diaphragm. The parasternal maintains and increases its active inspiratory shortening during augmented ventilation, despite high levels of diaphragm recruitment. Throughout hypercapnic ventilation, the parasternal contributes mechanically; it is not relegated to chest wall fixation.NEW & NOTEWORTHY This investigation directly compares neural activation of the parasternal intercostal muscle with the two distinct segments of the diaphragm, costal and crural, during room air and hypercapnic ventilation. During eupnea and hypercapnia, the parasternal intercostal muscle and costal diaphragm share a similar neural activation, whereas they both differ significantly from the crural diaphragm. The parasternal intercostal muscle maintains and increases active inspiratory mechanical action with shortening during ventilation, even with high levels of diaphragm recruitment.

Clinical application of a digital thoracic drainage system for objectifying and quantifying air leak versus the traditional vacuum system: a retrospective observational study.

BACKGROUND: Digital thoracic drainage systems have recently been introduced and widely used in clinical practices in developed countries. These systems can monitor intrathoracic pressure changes and air leaks in real time, and also allow for objective and quantitative analyses, which aid in managing patients with a prolonged persistent air leak into the pleural space. We investigated the feasibility and effectiveness of such a new device versus the traditional vacuum system for treating patients with pneumothorax. METHODS: Closed thoracostomy drainage was carried out on 100 adult patients with primary or secondary pneumothorax between January 2017 and December 2018. All the patients were aged ≥18 years and treated with a chest tube at a single medical center by the same cardiothoracic surgeons and intensivists. Patients who underwent closed thoracostomy drainage using an indwelling 24-French chest tube were divided into 2 groups immediately before closed thoracostomy: the digital thoracic drainage group (digital group, n=50) and the traditional analogue thoracic drainage group (analogue group, n=50). The detailed information about demographic data, treatment outcome, duration of indwelling catheterization., hospital days, cost-effectiveness and patient satisfaction was evaluated. We also evaluated whether digitally recorded intrapleural pressure changes and air leaks would predict chest tube removal timing and outcome. RESULTS: The baseline parameters of the 2 groups were comparable with no significant differences in sex, age, weight or body mass index. The mean hospital day was shorter in the digital group than in the analogue group (17.96±12.23 vs. 18.32±16.64, P=0.902), and there was no statistically significant difference in the hospital length of stay between the 2 groups. Air leaks through the chest tube and duration of chest tube indwelling hours showed no significant statistical differences between the digital and analogue groups (213.47±219.80 vs. 261.94±184.47, P=0.235 and 223.44±218.75 vs 275.29±186.06, P=0.205, respectively). Total drainage amount and ambulation time per day were significantly higher in the digital group than in the analogue group [209.62±139.63 vs. 162.48±80.42 (P=0.042) and 6.42±3.62 vs.3.94±1.74 (P<0.001), respectively]. Hours of full expansion were significantly shorter and sleep disturbance caused by the noise of chest tube drainage was less in the digital group than in the analogue group [25.64±14.55 vs. 46.52±25.53 (P<0.001) and 2.38±1.03 vs. 5.70±2.87 (P<0.001), respectively]. CONCLUSIONS: To date, there is no definite consensus and guidelines on the standardized digital suction system in pneumothorax. This study proposed the guidelines for the application of digital thoracic drainage systems in pneumothorax and also suggested that digital thoracic drainage systems might be a valuable tool to determine chest tube removal timing and reducing the length of hospital stay in patients with pneumothorax.

Limitations of surface EMG estimate of parasternal intercostal to infer neural respiratory drive.

BACKGROUND: Recently, surface EMG of parasternal intercostal muscle has been incorporated in the "ERS Statement of Respiratory Muscle Testing" as a clinical technique to monitor the neural respiratory drive (NRD). However, the anatomy of the parasternal muscle risks confounding EMG "crosstalk" activity from neighboring muscles. OBJECTIVES: To determine if surface "parasternal" EMG: 1) reliably estimates parasternal intercostal EMG activity, 2) is a valid surrogate expressing neural respiratory drive (NRD). METHODS: Fine wire electrodes were implanted into parasternal intercostal muscle in 20 severe COPD patients along with a pair of surface EMG electrodes at the same intercostal level. We recorded both direct fine wire parasternal EMG (EMGPARA) and surface estimated "parasternal" EMG (SurfEMGpara) simultaneously during resting breathing, volitional inspiratory maneuvers, apnoea with extraneous movement of upper extremity, and hypercapnic ventilation. RESULTS: Surface estimated "parasternal" EMG showed spurious "pseudobreathing" activity without any airflow while real parasternal EMG was silent, during apnoea with body extremity movement. Surface estimated "parasternal" EMG did not faithfully represent real measured parasternal EMG. Surface estimated "parasternal" EMG was significantly less active than directly measured parasternal EMG during all conditions including baseline, inspiratory capacity and hypercapnic ventilation. Bland-Altman analysis showed consistent bias between direct parasternal EMG recording and surface estimated EMG during stimulated breathing. CONCLUSION: Surface "parasternal" EMG does not consistently or reliably express EMG activity of parasternal intercostal as recorded directly by implanted fine wires. A chest wall surface estimate of parasternal intercostal EMG may not faithfully express NRD and is of limited utility as a biomarker in clinical applications.

Distinct neural-mechanical efficiency of costal and crural diaphragm during hypercapnia.

Classic physiology suggests that the two distinct diaphragm segments, costal and crural, are functionally different. It is not known if the two diaphragm muscles share a common neural mechanical activation. We hypothesized that costal and crural diaphragm are recruited differently during hypercapnic stimulated ventilation, and the EMG recordings of the esophageal crural diaphragm segment does not translate to the same level of mechanical shortening for costal and crural segments In 30 spontaneously breathing canines, without confounding anesthetic, we measured directly electrical activity and corresponding mechanical shortening of both the costal and crural diaphragm, at room air and during increasing hypercapnia. During hypercapnic ventilation, the costal diaphragm showed a predominant recruitment over the crural diaphragm. The distinct mechanical contribution of the costal segment was not due to a different level of neural activation between the two muscles as measured by segmental EMG activity. Thus, the two diaphragm segments exhibited a significantly different neural-mechanical relationship.

Aminophylline increases parasternal muscle action in awake canines.

The traditional theophylline bronchodilator, aminophylline, is still widely used, especially in the treatment of COPD. The effects of aminophylline on ventilation and action of the costal diaphragm have been previously defined, but other respiratory muscles - notably the chest wall, are not well determined. Therefore, we investigated the effects of aminophylline on the Parasternal intercostal, a key obligatory inspiratory muscle, examining muscle length, shortening and EMG. We studied 11 awake canines, chronically implanted with sonomicrometer crystals and fine-wire EMG electrodes in the parasternal muscle. Ventilatory parameters, muscle length (shortening), and moving average muscle EMG activity, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5 h after loading and ongoing infusion. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Parasternal baseline muscle length was entirely unchanged with aminophylline. Parasternal shortening increased significantly with aminophylline while corresponding parasternal EMG activity remained constant, consistent with increased contractility. Thus, in awake, intact mammals, aminophylline, in the usual therapeutic range, elicits increased ventilation and increased contractility of all primary inspiratory respiratory muscles, including both chest wall and diaphragm.

Costal and crural diaphragm function during sustained hypoxia in awake canines.

In humans and other mammals, isocapnic hypoxia sustained for 20-60 min exhibits a biphasic ventilation pattern: initial increase followed by a significant ventilatory decline ("roll-off") to a lesser intermediate plateau. During sustained hypoxia, the mechanical action and activity of the diaphragm have not been studied; thus we assessed diaphragm function in response to hypoxic breathing. Thirteen spontaneously breathing awake canines were exposed to moderate levels of sustained isocapnic hypoxia lasting 20-25 min (80 ± 2% pulse oximeter oxygen saturation). Breathing pattern and changes in muscle length and electromyogram (EMG) activity of the costal and crural diaphragm were continuously recorded. Mean tidal shortening and EMG activity of the costal and crural diaphragm exhibited an overall biphasic pattern, with initial brisk increase followed by a significant decline (P < 0.01). Although costal and crural shortening did not differ significantly with sustained hypoxia, this equivalence in segmental shortening occurred despite distinct and differing EMG activities of the costal and crural segments. Specifically, initial hypoxia elicited a greater costal EMG activity compared with crural (P < 0.05), whereas sustained hypoxia resulted in a lesser crural EMG decline/attenuation than costal (P < 0.05). We conclude that sustained isocapnic hypoxia elicits a biphasic response in both ventilation and diaphragmatic function and there is clear differential activation and contribution of the two diaphragmatic segments. This different diaphragm segmental action is consistent with greater neural activation of costal diaphragm during initial hypoxia, then preferential sparing of crural activation as hypoxia is sustained. NEW & NOTEWORTHY In humans and other mammals, during isocapnic hypoxia sustained for 20-60 min ventilation exhibits a biphasic pattern: initial increase followed by significant ventilatory decline ("roll-off"). During sustained hypoxia, the function of the diaphragm is unknown. This study demonstrates that the diaphragm reveals a biphasic action during the time-dependent hypoxic "roll-off" in ventilation. These results also highlight that the two diaphragm segments, costal and crural, show differing, distinctive contributions to diaphragm function during sustained hypoxia.

Ventilation and diaphragm activity during sustained hypoxia in awake canines.

In humans, isocapnic hypoxia sustained for 20-30 min elicits a biphasic ventilatory response with an initial increased peak followed by a roll-off to a lesser, intermediate plateau. However, it is uncertain if this hypoxic roll-off is common for all mammals, as canines have been a notable exception. We examined the effect of moderate isocapnic hypoxia (SpO2 80%) sustained for 20 min in 13 adult, awake, intact canines. The ventilatory response to sustained isocapnic hypoxia in these canines was not maintained: after an initial brisk response, ventilation declined significantly to an intermediate plateau. The hypoxic ventilatory decline occurred via a decrease in tidal volume, without change in breathing frequency. Distinct from airflow, costal diaphragm EMG showed a concurrent decline during sustained isocapnic hypoxia. However, the change in ventilation during sustained hypoxia in canines was very different from the response in humans. Although some decline in ventilation during sustained hypoxia may be common to all mammals, there are notable differences among species.