Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies.

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients.

AIMS: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. METHODS: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2 ) and FiO2 , and the World Health Organisation modified ordinal clinical scale. RESULTS: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P < .0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P = .17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P < .001). CONCLUSION: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and statistical analysis plan for an investigator-initiated international metatrial of randomised studies.

AIMS: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus' entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. METHODS: The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) metatrial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. ANALYSIS: We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. TRIAL REGISTRATION, ETHICS AND DISSEMINATION: The metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.

Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence.

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

The operating surgeon is an independent predictor of chest tube drainage following cardiac surgery.

OBJECTIVES: Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. DESIGN: Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. SETTING: Tertiary hospital. PARTICIPANTS: Two thousand five hundred seventy-five patients. INTERVENTIONS: Cardiac surgery. RESULTS: The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. CONCLUSIONS: The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes.

Cerebrovascular Responses in a Patient with Lundberg B Waves Following Subarachnoid Haemorrhage Assessed with a Novel Non-Invasive Brain Pulse Monitor: A Case Report.

Subarachnoid haemorrhage (SAH) can trigger a range of poorly understood cerebrovascular responses that may play a role in delayed cerebral ischemia. The brain pulse monitor is a novel non-invasive device that detects a brain photoplethysmography signal that provides information on intracranial pressure (ICP), compliance, blood flow and tissue oxygen saturation. We monitored the cerebrovascular responses in a patient with Lundberg B waves following a SAH. The patient presented with a Fischer grade 4 SAH that required urgent left posterior communicating artery aneurysm coiling and ventricular drain insertion. On hospital day 4 oscillations or spikes on the invasive ICP were noted, consistent with Lundberg B waves. Brain pulse monitoring demonstrated concurrent pulse waveform features consistent with reduced brain compliance and raised ICP over both brain hemispheres. Oxygen levels also demonstrated slow oscillations correlated with the ICP spikes. Brief infrequent episodes of reduced and absent brain pulses were also noted over the right hemisphere. Our findings suggest that the brain pulse monitor holds promise for early detection of delayed cerebral ischemia and could offer insights into the vascular mechanisms at play.

The association of blood transfusion with mortality after cardiac surgery: cause or confounding? (CME).

BACKGROUND: Bleeding into the chest is a life-threatening complication of cardiac surgery. Blood transfusion has been implicated as an important cause of harm associated with bleeding, based largely on studies demonstrating an independent association between transfusion and mortality. These studies did not, however, consider the possibility that bleeding may in itself be harmful, inasmuch as drains are inefficient at clearing blood from the chest and retained blood may compromise cardiac and lung function. STUDY DESIGN AND METHODS: We undertook a multivariate logistic regression analysis of the risk factors associated with mortality in 2599 consecutive patients undergoing cardiac surgery. Unlike previous studies the risk factors examined included the volume of chest tube drainage at 24 hours. A stratified analysis was also undertaken that compared the adjusted risk of death for patients exposed or not exposed to a postoperative blood transfusion. RESULTS: Blood transfusion was not an independent predictor of mortality (p=0.4). Chest tube drainage was the strongest independent predictor of mortality (p<0.001). In the stratified analysis, chest tube drainage remained an independent predictor of mortality for patients not exposed to a blood transfusion (p<0.01). Furthermore, the risk of death of these patients was no different from patients exposed to a blood transfusion (p=0.7 for interaction). CONCLUSIONS: Our results argue that for patients undergoing cardiac surgery bleeding contributes to mortality through mechanisms unrelated to blood transfusion.

Right ventricular pneumatosis and extensive multi-territory air emboli in an intravenous drug user: a case report.

Background: Air emboli are a life-threatening diagnosis, which may form through a range of mechanisms. In this case, we describe the case of extensive multi-territory air emboli in a patient with a history of intravenous drug abuse. Case summary: This case describes a 41-year-old male who presented with confusion following fall with long lie. He was diagnosed with hyperkalaemia, renal failure, rhabdomyolysis, and compartment syndrome, and he developed extensive multi-territory air emboli. Air embolism was identified in arterial, venous, subcutaneous, and mediastinal territories. Echocardiography demonstrated right ventricular dilation and dysfunction, consistent with air visualized in the right coronary artery on computed tomography. The patient was transferred to the intensive care unit for close cardiac and neurological monitoring and supportive organ care, and ultimately made an uneventful recovery by 6 weeks without apparent complications from the air emboli. Discussion: The presence of multi-territory air emboli has previously been described in the setting of surgery, manipulation of intravascular catheters, pulmonary barotrauma, and in sepsis with gas-forming organisms. It has not previously been reported in intravenous drug use or sterile rhabdomyolysis. Computed tomography imaging and echocardiography are useful to diagnose air emboli and their haemodynamic impact. Our patient's case provides a novel example of multi-territory air emboli in a unique scenario.

Assessment of a Non-Invasive Brain Pulse Monitor to Measure Intra-Cranial Pressure Following Acute Brain Injury.

Background: Intracranial pressure (ICP) monitoring requires placing a hole in the skull through which an invasive pressure monitor is inserted into the brain. This approach has risks for the patient and is expensive. We have developed a non-invasive brain pulse monitor that uses red light to detect a photoplethysmographic (PPG) signal arising from the blood vessels on the brain's cortical surface. The brain PPG and the invasive ICP waveform share morphological features which may allow measurement of the intracranial pressure. Methods: We enrolled critically ill patients with an acute brain injury with invasive ICP monitoring to assess the new monitor. A total of 24 simultaneous invasive ICP and brain pulse monitor PPG measurements were undertaken in 12 patients over a range of ICP levels. Results: The waveform morphologies were similar for the invasive ICP and brain pulse monitor PPG approach. Both methods demonstrated a progressive increase in the amplitude of P2 relative to P1 with increasing ICP levels. An automated algorithm was developed to assess the PPG morphological features in relation to the ICP level. A correlation was demonstrated between the brain pulse waveform morphology and ICP levels, R2=0.66, P < 0.001. Conclusion: The brain pulse monitor's PPG waveform demonstrated morphological features were similar to the invasive ICP waveform over a range of ICP levels, these features may provide a method to measure ICP levels. Trial Registration: ACTRN12620000828921.

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations.

BACKGROUND: Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. METHOD: We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans. RESULTS: The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings. CONCLUSION: Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.

Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial.

INTRODUCTION: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation. METHODS: Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization. RESULTS: Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events. CONCLUSIONS: Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings. TRIAL REGISTRATION: The Australian Clinical Trials Registry (ACTR-12608000121369).

Assessment of a Non Invasive Brain Oximeter in Volunteers Undergoing Acute Hypoxia.

INTRODUCTION: Research in traumatic brain injury suggests better patient outcomes when invasive oxygen monitoring is used to detect and correct episodes of brain hypoxia. Invasive brain oxygen monitoring is, however, not routinely used due to the risks, costs and technical challengers. We are developing a non-invasive brain oximeter to address these limitations. The monitor uses the principles of pulse oximetry to record a brain photoplethysmographic waveform and oxygen saturations. We undertook a study in volunteers to assess the new monitor. PATIENTS AND METHODS: We compared the temporal changes in the brain and skin oxygen saturations in six volunteers undergoing progressive hypoxia to reach arterial saturations of 70%. This approach provides a method to discriminate potential contamination of the brain signal by skin oxygen levels, as the responses in brain and skin oxygen saturations are distinct due to the auto-regulation of cerebral blood flow to compensate for hypoxia. Conventional pulse oximetry was used to assess skin oxygen levels. Blood was also collected from the internal jugular vein and correlated with the brain oximeter oxygen levels. RESULTS: At baseline, a photoplethysmographic waveform consistent with that expected from the brain was obtained in five subjects. The signal was adequate to assess oxygen saturations in three subjects. During hypoxia, the brain's oximeter oxygen saturation fell to 74%, while skin saturation fell to 50% (P<0.0001). The brain photoplethysmographic waveform developed a high-frequency oscillation of ~7 Hz, which was not present in the skin during hypoxia. A weak correlation between the brain oximeter and proximal internal jugular vein oxygen levels was demonstrated, R2=0.24, P=0.01. CONCLUSION: Brain oximeter oxygen saturations were relatively well preserved compared to the skin during hypoxia. These findings are consistent with the expected physiological responses and suggest skin oxygen levels did not markedly contaminate the brain oximeter signal.

Nebulized Heparin in Burn Patients with Inhalation Trauma-Safety and Feasibility.

BACKGROUND: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. METHODS: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. RESULTS: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. CONCLUSION: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients.

Assessment of a Non-Invasive Brain Oximeter in a Sheep Model of Acute Brain Injury.

INTRODUCTION: Evidence suggests treatments guided by brain oxygen levels improve patient outcomes following severe traumatic brain injury; however, brain oxygen levels are not routinely monitored as an effective non-invasive method has not been established. We undertook a study, in a sheep model of acute brain injury, to assess a new non-invasive brain oximeter. The monitor uses the principles of pulse oximetry to record a pulse and oxygen levels. METHODS: We studied 8 sheep. An acute increase in intracranial pressure was induced with an injection of blood into the cranial vault. The temporal changes in the brain oximeter, intracranial pressure and cerebral perfusion pressure were recorded. Simultaneous conventional skin pulse oximetry was also recorded to assess the possible influence of skin blood flow on the brain oximeter signal. RESULTS: At baseline, a pulsatile waveform consistent with the brain circulation was obtained in 7 animals. The baseline brain pulse was quite distinct from the simultaneous conventional skin pulse and similar in shape to a central venous pressure waveform. Injection of blood into the cranial vault triggered an immediate increase in intracranial pressure and fall in cerebral perfusion pressure, by 60-s cerebral perfusion pressure recovered. The brain oximeter oxygen levels demonstrated similar changes with an immediate fall and recovery by 60 s. Periods of high intracranial pressure were also associated with high-frequency oscillations in the brain pulse waveform; there was, however, no change in the conventional skin pulse oximeter pulse waveform. CONCLUSION: The brain oximeter detected acute changes in both oxygen levels and the brain pulse waveform following an increase in intracranial pressure levels. The brain oximeter could assist clinicians in the management of acute brain injury.

Elevated pulmonary dead space and coagulation abnormalities suggest lung microvascular thrombosis in patients undergoing cardiac surgery.

OBJECTIVE: Inflammation has been shown to trigger microvascular thrombosis. Patients undergoing cardiac surgery sustain significant inflammatory insults to the lungs and in addition are routinely given anti-fibrinolytic agents to promote thrombosis. In view of these risk factors we investigated if evidence of pulmonary microvascular thrombosis occurs following cardiac surgery and, if so, whether a pre-operative heparin infusion may limit this. DESIGN: Double-blind randomised controlled trial. SETTING: Tertiary university affiliated hospital. PATIENTS: Twenty patients undergoing elective cardiac surgery. INTERVENTIONS: Patients were randomised to receive a pre-operative heparin infusion or placebo. All patients were administered aprotinin. MEASUREMENTS AND RESULTS: Pulmonary microvascular obstruction was estimated by measuring the alveolar dead-space fraction. Pulmonary coagulation activation was estimated by measuring the ratio of prothrombin fragment levels in radial and pulmonary arterial blood. Systemic tissue plasminogen activator (t-PA) levels were also assessed. In the placebo group cardiac surgery triggered increased alveolar dead-space fraction levels and the onset of prothrombin fragment production in the pulmonary circulation. Administration of pre-operative heparin was associated with a lower alveolar dead-space fraction (p < 0.05) and reduced prothrombin fragment production in the pulmonary circulation (p < 0.05). Pre-operative heparin also increased baseline t-PA levels (p < 0.05). CONCLUSION: The changes in the alveolar dead-space fraction and pulmonary coagulation activation suggest that pulmonary microvascular thrombosis develops during cardiac surgery and this may be limited by a pre-operative heparin infusion.

A phase 1 trial of nebulised heparin in acute lung injury.

INTRODUCTION: Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI. METHODS: An open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose. RESULTS: No serious adverse events occurred for any dose. The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses. CONCLUSION: Administration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects. TRIAL REGISTRATION: Australian Clinical trials registry ACTRN12606000388516.

Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies.

Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects.