Study of risk factors for injuries due to cardiopulmonary resuscitation with special focus on the role of the heart: A machine learning analysis of a prospective registry with multiple sources of information (ReCaPTa Study).

Background: The study of thoracic injuries and biomechanics during CPR requires detailed studies that are very scarce. The role of the heart in CPR biomechanics has not been determined. This study aimed to determine the risk factors importance for serious ribcage damage due to CPR. Methods: Data were collected from a prospective registry of out-of-hospital cardiac arrest between April 2014 and April 2017. This study included consecutive out-of-hospital CPR attempts undergoing an autopsy study focused on CPR injuries. Cardiac mass ratio was defined as the ratio of real to expected heart mass. Pearson's correlation coefficient was used to select clinically relevant variables and subsequently classification tree models were built. The Gini index was used to determine the importance of the associated serious ribcage damage factors. The LUCAS® chest compressions device forces and the cardiac mass were analyzed by linear regression. Results: Two hundred CPR attempts were included (133 manual CPR and 67 mechanical CPR). The mean age of the sample was 60.4 ± 13.5, and 56 (28%) were women. In all, 65.0% of the patients presented serious ribcage damage. From the classification tree build with the clinically relevant variables, age (0.44), cardiac mass ratio (0.26), CPR time (0.22), and mechanical CPR (0.07), in that order, were the most influential factors on serious ribcage damage. The chest compression forces were greater in subjects with higher cardiac mass. Conclusions: The heart plays a key role in CPR biomechanics being cardiac mass ratio the second most important risk factor for CPR injuries.

Transthoracic impedance variability to assess quality of chest compression in out-of-hospital cardiac arrest.

BACKGROUND: Chest compression is a lifesaving intervention in out-of-hospital cardiac arrest (OHCA), but the optimal metrics to assess its quality have yet to be identified. The objective of this study was to investigate whether a new parameter, that is, the variability of the chest compression-generated transthoracic impedance (TTI), namely ImpCC , which measures the consistency of the chest compression maneuver, relates to resuscitation outcome. METHODS: This multicenter observational, retrospective study included OHCAs with shockable rhythm. ImpCC variability was evaluated with the power spectral density analysis of the TTI. Multivariate regression model was used to examine the impact of ImpCC variability on defibrillation success. Secondary outcome measures were return of spontaneous circulation and survival. RESULTS: Among 835 treated OHCAs, 680 met inclusion criteria and 565 matched long-term outcomes. ImpCC was significantly higher in patients with unsuccessful defibrillation compared to those with successful defibrillation (p = .0002). Lower ImpCC variability was associated with successful defibrillation with an odds ratio (OR) of 0.993 (95% confidence interval [95% CI], 0.989-0.998, p = .003), while the standard chest compression fraction (CCF) was not associated (OR 1.008 [95 % CI, 0.992-1.026, p = .33]). Neither ImpCC nor CCF was associated with long-term outcomes. CONCLUSIONS: In this population, consistency of chest compression maneuver, measured by variability in TTI, was an independent predictor of defibrillation outcome. ImpCC may be a useful novel metrics for improving quality of care in OHCA.

Chest wall mechanics during mechanical chest compression and its relationship to CPR-related injuries and survival.

Aim: To determine compression force variation (CFV) during mechanical cardiopulmonary resuscitation (CPR) and its relationship with CPR-related injuries and survival. Methods: Adult non-traumatic OHCA patients who had been treated with mechanical CPR were evaluated for CPR-related injuries using chest X-rays, thoracic computed tomography or autopsy. The CFV exerted by the LUCAS 2 device was calculated as the difference between the maximum and the minimum force values and was categorised into three different groups (high positive CFV ≥ 95 newton (N), high negative CFV ≤ -95 N, and low variation for intermediate CFV). The CFV was correlated with the CPR injuries findings and survival data. Results: Fifty-two patients were included. The median (IQR) age was 57 (49-66) years, and 13 (25%) cases survived until hospital admission. High positive CFV was found in 21 (40.4%) patients, high negative CFV in 9 (17.3%) and a low CFV in 22 (42.3%). The median (IQR) number of rib fractures was higher in the high positive and negative CFV groups compared with the low CFV group [7(1-9) and 9 (4-11) vs 0 (0-6) (p = 0.021)]. More bilateral fracture cases were found in the high positive and negative CFV groups [16 (76.2%) and 6 (66.7%) vs 6 (27.3%) (p = 0.004)]. In the younger half of the sample more patients survived until hospital admission in the low CFV group compared with the high CFV groups [5 (41.7%) vs 1 (7.1%) (p = 0.037)]. Conclusions: High CFV was associated with ribcage injuries. In the younger patients low CFV was associated with survival until hospital admission.

Mechanical active compression-decompression versus standard mechanical cardiopulmonary resuscitation: A randomised haemodynamic out-of-hospital cardiac arrest study.

BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (ACD-CPR) utilises a suction cup to lift the chest-wall actively during the decompression phase (AD). We hypothesised that mechanical ACD-CPR (Intervention), with AD up to 30 mm above the sternal resting position, would generate better haemodynamic results than standard mechanical CPR (Control). METHODS: This out-of-hospital adult non-traumatic cardiac arrest trial was prospective, block-randomised and non-blinded. We included intubated patients with capnography recorded during mechanical CPR. Exclusion criteria were pregnancy, prisoners, and prior chest surgery. The primary endpoint was maximum tidal carbon dioxide partial pressure (pMTCO2) and secondary endpoints were oxygen saturation of cerebral tissue (SctO2), invasive arterial blood pressures and CPR-related injuries. Intervention device lifting force performance was categorised as Complete AD (≥30 Newtons) or Incomplete AD (≤10 Newtons). Haemodynamic data, analysed as one measurement for each parameter per ventilation (Observation Unit, OU) with non-linear regression statistics are reported as mean (standard deviation). A two-sided p-value < 0.05 was considered as statistically significant. RESULTS: Of 221 enrolled patients, 210 were deemed eligible (Control 109, Intervention 101). The Control vs. Intervention results showed no significant differences for pMTCO2: 29(17) vs 29(18) mmHg (p = 0.86), blood pressures during compressions: 111(45) vs. 101(68) mmHg (p = 0.93) and decompressions: 21(20) vs. 18(18) mmHg (p = 0.93) or for SctO2%: 55(36) vs. 57(9) (p = 0.42). The 48 patients who received Complete AD in > 50% of their OUs had higher SctO2 than Control patients: 58(11) vs. 55(36)% (p < 0.001). CONCLUSIONS: Mechanical ACD-CPR provided similar haemodynamic results to standard mechanical CPR. The Intervention device did not consistently provide Complete AD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT number): NCT02479152. The Haemodynamic Effects of Mechanical Standard and Active Chest Compression-decompression During Out-of-hospital CPR.

Metrics of mechanical chest compression device use in out-of-hospital cardiac arrest.

OBJECTIVE: The quality of cardiopulmonary resuscitation (CPR) affects outcomes from cardiac arrest, yet manual CPR is difficult to administer. Although mechanical CPR (mCPR) devices offer high quality CPR, only limited data describe their deployment, their interaction with standard manual CPR (sCPR), and the consequent effects on chest compression continuity and patient outcomes. We sought to describe the interaction between sCPR and mCPR and the impact of the sCPR-mCPR transition upon outcomes in adult out-of-hospital cardiac arrest (OHCA). METHODS: We analyzed all adult ventricular fibrillation OHCA treated by the Anchorage Fire Department (AFD) during calendar year 2016. AFD protocols include the immediate initiation of sCPR upon rescuer arrival and transition to mCPR, guided by patient status. We compared CPR timing, performance, and outcomes between those receiving sCPR only and those receiving sCPR transitioning to mCPR (sCPR + mCPR). RESULTS: All 19 sCPR-only patients achieved return of spontaneous circulation (ROSC) after a median of 3.3 (interquartile range 2.2-5.1) minutes. Among 30 patients remaining pulseless after sCPR (median 6.9 [5.3-11.0] minutes), transition to mCPR occurred with a median chest compression interruption of 7 (5-13) seconds. Twenty-one of 30 sCPR + mCPR patients achieved ROSC after a median of 11.2 (5.7-23.8) additional minutes of mCPR. Survival differed between groups: sCPR only 14/19 (74%) versus sCPR + mCPR 13/30 (43%), P = 0.045. CONCLUSION: In this series, transition to mCPR occurred in patients unresponsive to initial sCPR with only brief interruptions in chest compressions. Assessment of mCPR must consider the interactions with sCPR.

LUCAS Versus Manual Chest Compression During Ambulance Transport: A Hemodynamic Study in a Porcine Model of Cardiac Arrest.

Background Mechanical chest compression (CC) is currently suggested to deliver sustained high-quality CC in a moving ambulance. This study compared the hemodynamic support provided by a mechanical piston device or manual CC during ambulance transport in a porcine model of cardiopulmonary resuscitation. Methods and Results In a simulated urban ambulance transport, 16 pigs in cardiac arrest were randomized to 18 minutes of mechanical CC with the LUCAS (n=8) or manual CC (n=8). ECG, arterial and right atrial pressure, together with end-tidal CO2 and transthoracic impedance curve were continuously recorded. Arterial lactate was assessed during cardiopulmonary resuscitation and after resuscitation. During the initial 3 minutes of cardiopulmonary resuscitation, the ambulance was stationary, while then proceeded along a predefined itinerary. When the ambulance was stationary, CC-generated hemodynamics were equivalent in the 2 groups. However, during ambulance transport, arterial and coronary perfusion pressure, and end-tidal CO2 were significantly higher with mechanical CC compared with manual CC (coronary perfusion pressure: 43±4 versus 18±4 mmHg; end-tidal CO2: 31±2 versus 19±2 mmHg, P<0.01 at 18 minutes). During cardiopulmonary resuscitation, arterial lactate was lower with mechanical CC compared with manual CC (6.6±0.4 versus 8.2±0.5 mmol/L, P<0.01). During transport, mechanical CC showed greater constancy compared with the manual CC, as represented by a higher CC fraction and a lower transthoracic impedance curve variability ( P<0.01). All animals in the mechanical CC group and 6 (75%) in the manual one were successfully resuscitated. Conclusions This model adds evidence in favor of the use of mechanical devices to provide ongoing high-quality CC and tissue perfusion during ambulance transport.

Haemodynamic outcomes during piston-based mechanical CPR with or without active decompression in a porcine model of cardiac arrest.

BACKGROUND: Experimental active compression-decompression (ACD) CPR is associated with increased haemodynamic outcomes compared to standard mechanical chest compressions. Since no clinically available mechanical chest compression device is capable of ACD-CPR, we modified the LUCAS 2 (Physio-Control, Lund, Sweden) to deliver ACD-CPR, hypothesising it would improve haemodynamic outcomes compared with standard LUCAS CPR on pigs with cardiac arrest. METHODS: The modified LUCAS delivering 5 cm compressions with or without 2 cm active decompression above anatomical chest level was studied in a randomized crossover design on 19 Norwegian domestic pigs. VF was electrically induced and untreated for 2 min. Each pig received ACD-CPR and standard mechanical CPR in three 180-s. phases. We measured aortic, right atrial, coronary perfusion, intracranial and oesophageal pressure, cerebral and carotid blood flow and cardiac output. Two-sided paired samples t-test was used for continuous parametric data and Wilcoxon test for non-parametric data. P < 0.05 was considered significant. RESULTS: Due to injuries/device failure, the experimental protocol was completed in nine of 19 pigs. Cardiac output (l/min, median, (25, 75-percentiles): 1.5 (1.1, 1.7) vs. 1.1 (0.8, 1.5), p < 0.01), cerebral blood flow (AU, 297 vs. 253, mean difference: 44, 95% CI; 14-74, p = 0.01), and carotid blood flow (l/min, median, (25, 75-percentiles): 97 (70, 106) vs. 83 (57, 94), p < 0.01) were higher during ACD-CPR compared to standard mechanical CPR. Coronary perfusion pressure (CPP) trended towards higher in end decompression phase. CONCLUSION: Cardiac output and brain blood flow improved with mechanical ACD-CPR and CPP trended towards higher during end-diastole compared to standard LUCAS CPR.

Outcome among VF/VT patients in the LINC (LUCAS IN cardiac arrest) trial-A randomised, controlled trial.

INTRODUCTION: The LINC trial evaluated two ALS-CPR algorithms for OHCA patients, consisting of 3min' mechanical chest compression (LUCAS) cycles with defibrillation attempt through compressions vs. 2min' manual compressions with compression pause for defibrillation. The PARAMEDIC trial, using 2min' algorithm found worse outcome for patients with initial VF/VT in the LUCAS group and they received more adrenalin compared to the manual group. We wanted to evaluate if these algorithms had any outcome effect for patients still in VF/VT after the initial defibrillation and how adrenalin timing impacted it. METHOD: Both groups received manual chest compressions first. Based on non-electronic CPR process documentation, outcome, neurologic status and its relation to CPR duration prior to the first detected return of spontaneous circulation (ROSC), time to defibrillation and adrenalin given were analysed in the subgroup of VF/VT patients. RESULTS: Seven hundred and fifty-seven patients had still VF/VT after initial chest compressions combined with a defibrillation attempt (374 received mechanical CPR) or not (383 received manual CPR). No differences were found for ROSC (mechanical CPR 58.3% vs. manual CPR 58.6%, p=0.94), or 6-month survival with good neurologic outcome (mechanical CPR 25.1% vs. manual CPR 23.0%, p=0.50). A significant difference was found regarding the time from start of manual chest compression to the first defibrillation (mechanical CPR: 4 (2-5) min vs manual CPR 3 (2-4) min, P<0.001). The time from the start of manual chest compressions to ROSC was longer in the mechanical CPR group. CONCLUSIONS: No difference in short- or long-term outcomes was found between the 2 algorithms for patients still in VF/VT after the initial defibrillation. The time to the 1st defibrillation and the interval between defibrillations were longer in the mechanical CPR group without impacting the overall outcome. The number of defibrillations required to achieve ROSC or adrenalin doses did not differ between the groups.

Physiologic effect of repeated adrenaline (epinephrine) doses during cardiopulmonary resuscitation in the cath lab setting: A randomised porcine study.

BACKGROUND: This porcine study was designed to explore the effects of repetitive intravenous adrenaline doses on physiologic parameters during CPR. METHODS: Thirty-six adult pigs were randomised to four injections of: adrenaline 0.02 mg(kgdose)(-1), adrenaline 0.03 mg(kgdose)(-1) or saline control. The effect on systolic, diastolic and mean arterial blood pressure, cerebral perfusion pressure (CePP), end tidal carbon dioxide (ETCO2), arterial oxygen saturation via pulse oximetry (SpO2), cerebral tissue oximetry (SctO2), were analysed immediately prior to each injection and at peak arterial systolic pressure and arterial blood gases were analysed at baseline and after 15 min. RESULT: In the group given 0.02 mg(kgdose)(-1), there were increases in all arterial blood pressures at all 4 pressure peaks but CePP only increased significantly after peak 1. A decrease in ETCO2 following peak 1 and 2 was observed. SctO2 and SpO2 were lowered following injection 2 and beyond. In the group given a 0.03 mg(kgdose)(-1), all ABP's increased at the first 4 pressure peaks but CePP only following 3 pressure peaks. Lower ETCO2, SctO2 and SpO2 were seen at peak 1 and beyond. In the two adrenaline groups, pH and Base Excess were lower and lactate levels higher compared to baseline as well as compared to the control. CONCLUSION: Repetitive intravenous adrenaline doses increased ABP's and to some extent also CePP, but significantly decreased organ and brain perfusion. The institutional protocol number: Malmö/Lund Committee for Animal Experiment Ethics, approval reference number: M 192-10.

Mechanical chest compressions in the coronary catheterization laboratory to facilitate coronary intervention and survival in patients requiring prolonged resuscitation efforts.

BACKGROUND: Resuscitation after cardiac arrest (CA) in the catheterization laboratory (cath-lab) using mechanical chest compressions (CC) during simultaneous percutaneous coronary intervention (PCI) is a strong recommendation in the 2015 European Resuscitation Council (ERC) guidelines. This study aimed at re-evaluating survival to hospital discharge and assess long term outcome in this patient population. METHODS: Patients presenting at the cath lab with spontaneous circulation, suffering CA and requiring prolonged mechanical CC during cath lab procedures between 2009 and 2013 were included. Circumstances leading to CA, resuscitation parameters and outcomes were evaluated within this cohort. For comparison, patients needing prolonged manual CC in the cath lab in the pre-mechanical CC era were evaluated. Six-month and one year survival with a mechanical CC treatment strategy from 2004 to 2013 was also evaluated. RESULTS: Thirty-two patients were included between 2009 and 2013 (24 ST-elevation myocardial infarction (STEMI), 4 non-STEMI, 2 planned PCI, 1 angiogram and 1 intra-aortic counter pulsation balloon pump insertion). Twenty were in cardiogenic shock prior to inclusion. Twenty-five were successfully treated with PCI. Median mechanical CC duration for the total cohort (n = 32) was 34 min (range 5-90), for the 15 patients with circulation discharged from the cath-lab, 15 min (range 5-90), and for the eight discharged alive from hospital, 10 min (range 5-52). Twenty-five percent survived with good neurological outcome at hospital discharge. Ten patients treated with manual CC were included with one survivor. DISCUSSION: Eighty-seven percent of the patients included in the mechanical CC cohort had their coronary or cardiac intervention performed during mechanical CC with an 80 % success rate. This shows that the use of mechanical CC during an intervention does not seem to impair the interventional result substantially. The survival rate after one year was 87 %. CONCLUSIONS: Among patients suffering CA treated with mechanical CC in the cath-lab, 25% had a good neurological outcome at hospital discharge compared to 10% treated with manual CC. Long term survival in patients discharged from hospital is good.

Force and depth of mechanical chest compressions and their relation to chest height and gender in an out-of-hospital setting.

INTRODUCTION: The LUCAS 2 device stores technical data that documents the chest compression process. We analyzed chest wall dimensions and mechanics stored during chest compressions on humans using data gathered with the LUCAS 2 device. METHODS: Data from LUCAS 2 devices used in out-of-hospital cardiac arrest were downloaded with dedicated proprietary software and matched to the corresponding patient data. Cases were included only if the suction cup was placed correctly, if it was not realigned during the first 5 min of chest compressions, and if no other anomaly in device use was noted. Trauma cases were excluded. RESULTS: Ninety-five patients were included. All patients received manual cardiopulmonary resuscitation prior to the application of the device. The mean (SD) chest height was 232 (25)mm for males and 209 (26)mm for females (P < 0.001). The mean (min-max) compression depth in patients with chest height >185 mm was 53 (50-55)mm, corresponding with 19-28% of the chest diameter. The mean force required to achieve the compression depth of 53 mm ranged between 219 and 568 N. No correlation was found between chest height and force to reach 53 mm depth (females: R(2) = 0.001, males: R(2) = 0.007). CONCLUSION: There was a large variation of the required force to achieve a compression depth of 53 mm. No correlation was seen between chest height and maximum force required to compress the chest 53 mm.

The study protocol for the LINC (LUCAS in cardiac arrest) study: a study comparing conventional adult out-of-hospital cardiopulmonary resuscitation with a concept with mechanical chest compressions and simultaneous defibrillation.

BACKGROUND: The LUCAS™ device delivers mechanical chest compressions that have been shown in experimental studies to improve perfusion pressures to the brain and heart as well as augmenting cerebral blood flow and end tidal CO2, compared with results from standard manual cardiopulmonary resuscitation (CPR). Two randomised pilot studies in out-of-hospital cardiac arrest patients have not shown improved outcome when compared with manual CPR. There remains evidence from small case series that the device can be potentially beneficial compared with manual chest compressions in specific situations. This multicentre study is designed to evaluate the efficacy and safety of mechanical chest compressions with the LUCAS™ device whilst allowing defibrillation during on-going CPR, and comparing the results with those of conventional resuscitation. METHODS/DESIGN: This article describes the design and protocol of the LINC-study which is a randomised controlled multicentre study of 2500 out-of-hospital cardiac arrest patients. The study has been registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00609778?term=LINC&rank=1). RESULTS: Primary endpoint is four-hour survival after successful restoration of spontaneous circulation. The safety aspect is being evaluated by post mortem examinations in 300 patients that may reflect injuries from CPR. CONCLUSION: This large multicentre study will contribute to the evaluation of mechanical chest compression in CPR and specifically to the efficacy and safety of the LUCAS™ device when used in association with defibrillation during on-going CPR.

Atrial fibrillatory rate and risk of stroke in atrial fibrillation.

AIMS: In atrial fibrillation (AF), a relation between electrocardiogram (ECG) parameters such as fibrillatory wave amplitude and stroke has been sought with conflicting results. In this study, we tested the hypothesis that the atrial fibrillatory rate of surface ECG lead V1 is related to stroke risk and may consequently be helpful for identifying high-risk patients. METHODS AND RESULTS: Atrial fibrillatory rate of 79 consecutive patients with AF and embolic stroke (age 83 +/- 7 years, 41% male) was compared with those of a matched AF population without stroke (n = 79). Atrial fibrillatory rate was determined from the surface ECG using spatiotemporal QRST cancellation and time-frequency analysis of lead V1. There was no significant difference in any clinical or echocardiographic variable in patients with stroke compared with AF controls without stroke. Atrial fibrillatory rate measured 373 +/- 55 fibrillations per minute (fpm; range 235-505 fpm) in the entire population. There was no fibrillatory rate difference between stroke patients (369 +/- 54 fpm, range 256-505 fpm) and AF controls without stroke (378 +/- 56 fpm, range 235-488 fpm). There was an inverse correlation between fibrillatory rate and age (R = -0.219, P = 0.006). Individuals aged >or=85 years had a significantly lower fibrillatory rate (356 +/- 44 fpm) than individuals aged 65-74 years (384 +/- 56 fpm, P = 0.033) and individuals aged 75-84 years (384 +/- 60 fpm, P = 0.016). In those subgroups, fibrillatory rates were, however, also similar in stroke patients and AF controls. CONCLUSION: Atrial fibrillatory rate obtained from surface ECG lead V1 is not a risk marker for stroke in AF.

Changes in clot lysis levels of reteplase and streptokinase following continuous wave ultrasound exposure, at ultrasound intensities following attenuation from the skull bone.

BACKGROUND: Ultrasound (US) has been used to enhance thrombolytic therapy in the treatment of stroke. Considerable attenuation of US intensity is however noted if US is applied over the temporal bone. The aim of this study was therefore to explore possible changes in the effect of thrombolytic drugs during low-intensity, high-frequency continuous-wave ultrasound (CW-US) exposure. METHODS: Clots were made from fresh venous blood drawn from healthy volunteers. Each clot was made from 1.4 ml blood and left to coagulate for 1 hour in a plastic test-tube. The thrombolytic drugs used were, 3600 IU streptokinase (SK) or 0.25 U reteplase (r-PA), which were mixed in 160 ml 0.9% NaCl solution. Continuous-wave US exposure was applied at a frequency of 1 MHz and intensities ranging from 0.0125 to 1.2 W/cm2. For each thrombolytic drug (n = 2, SK and r-PA) and each intensity (n = 9) interventional clots (US-exposed, n = 6) were submerged in thrombolytic solution and exposed to CW-US while control clots (also submerged in thrombolytic solution, n = 6) were left unexposed to US.To evaluate the effect on clot lysis, the haemoglobin (Hb) released from each clot was measured every 20 min for 1 hour (20, 40 and 60 min). The Hb content (mg) released was estimated by spectrophotometry at 540 nm. The difference in effect on clot lysis was expressed as the difference in the amount of Hb released between pairs of US-exposed clots and control clots. Statistical analysis was performed using Wilcoxon's signed rank test. RESULTS: Continuous-wave ultrasound significantly decreased the effects of SK at intensities of 0.9 and 1.2 W/cm2 at all times (P < 0.05). Continuous-wave ultrasound significantly increased the effects of r-PA on clot lysis following 20 min exposure at 0.9 W/cm2 and at 1.2 W/cm2, following 40 min exposure at 0.3, 0.6, 0.9 and at 1.2 W/cm2, and following 60 min of exposure at 0.05 0.3, 0.6, 0.9 and at 1.2 W/cm2 (all P < 0.05). CONCLUSION: Increasing intensities of CW-US exposure resulted in increased clot lysis of r-PA-treated blood clots, but decreased clot lysis of SK-treated clots.

Direct action on the molecule is one of several mechanisms by which ultrasound enhances the fibrinolytic effects of reteplase.

Enhanced fibrinolytic reperfusion therapy may improve the outcome in embolic stroke, where ultrasound exposure has been shown to be one option. We recently verified that the fibrinolytic properties of streptokinase were modulated following ultrasound exposure of the molecule. We have now explored this possibility following ultrasound exposure of the reteplase molecule. The effects on clot lysis of reteplase and ultrasound both separately and in combination were studied by evaluating cumulated release of haemoglobin from whole blood clots following 1 h of exposure. Specifically, we investigated how clot lysis was modulated following pulsed 1 MHz ultrasound pre-exposure of the reteplase solution at intensities ranging between 0.125 and 4 W/cm2 spatial-average temporal-average intensity (SATA) and the effects of reteplase following 1 h of pre-exposure of clots to ultrasound at high intensity (4 W/cm2SATA). Significant enhancement of clot lysis during concomitant reteplase and pulsed ultrasound exposure were observed in two intensity ranges: 0.125-0.25 and 2-4 W/cm2SATA. Pre-exposing reteplase solution to ultrasound significantly increased clot lysis only in the lower intensity range. At high ranges, pre-exposure of clots to ultrasound was followed by an increased fibrinolytic action of reteplase. Pre-exposing reteplase solution to low-intensity ultrasound induced changes in the reteplase molecule that enhanced its fibrinolytic effects. Although this effect disappeared at moderately higher ultrasound intensity, the pre-exposure of clots to ultrasound of higher intensity induced increased fibrinolytic effects of reteplase solution.

Low-energy ultrasound exposure of the streptokinase molecule may enhance but also attenuate its fibrinolytic properties.

INTRODUCTION: This study explores the mechanisms of ultrasound-enhanced fibrinolysis by investigating the effects of pre-exposure to pulsed high-frequency, low-energy ultrasound on the fibrinolytic properties of streptokinase. MATERIALS AND METHODS: Fibrinolytic activity was measured as haemoglobin release from blood clots. The fibrinolytic effects of streptokinase and ultrasound separately and in combination were studied by evaluating cumulative percentages of haemoglobin release following 1 h of exposure using two clots, one for intervention and the other concomitantly as control. In particular, the effects of exposure to ultrasound on clot-free streptokinase solution were compared to those of concomitant exposures of streptokinase solution with clot. The exposures were made at a frequency of 1 MHz (10% duty cycle) and at three intensity levels (0.5, 1.0 and 4.0 W/cm2 intensity I(SATA)). RESULTS: Increased fibrinolysis (31.2%, P=0.028) was observed after concomitant ultrasound exposure of clot and streptokinase solution at 0.5 W/cm2 intensity. Compared to unexposed streptokinase solution, the lytic effect following exposure of streptokinase solution to ultrasound was significantly increased (32.7%, P=0.002). This enhancement effect disappeared at intensity 1 W/cm2, whilst further increase to 4.0 W/cm2 inhibited the lytic effect of streptokinase, both during concomitant exposure (-25.2%, P=0.028) and after pre-exposure of streptokinase solution to ultrasound (-25.4%, P=0.002). CONCLUSION: The fibrinolytic property of streptokinase is modulated by exposure to pulsed ultrasound of frequency 1 MHz, being enhanced at low intensity and inhibited at high intensity.

Can pulsed ultrasound increase tissue damage during ischemia? A study of the effects of ultrasound on infarcted and non-infarcted myocardium in anesthetized pigs.

BACKGROUND: The same mechanisms by which ultrasound enhances thrombolysis are described in connection with non-beneficial effects of ultrasound. The present safety study was therefore designed to explore effects of beneficial ultrasound characteristics on the infarcted and non-infarcted myocardium. METHODS: In an open chest porcine model (n = 17), myocardial infarction was induced by ligating a coronary diagonal branch. Pulsed ultrasound of frequency 1 MHz and intensity 0.1 W/cm2 (ISATA) was applied during one hour to both infarcted and non-infarcted myocardial tissue. These ultrasound characteristics are similar to those used in studies of ultrasound enhanced thrombolysis. Using blinded assessment technique, myocardial damage was rated according to histopathological criteria. RESULTS: Infarcted myocardium exhibited a significant increase in damage score compared to non-infarcted myocardium: 6.2 +/- 2.0 vs. 4.3 +/- 1.5 (mean +/- standard deviation), (p = 0.004). In the infarcted myocardium, ultrasound exposure yielded a further significant increase of damage scores: 8.1 +/- 1.7 vs. 6.2 +/- 2.0 (p = 0.027). CONCLUSION: Our results suggest an instantaneous additive effect on the ischemic damage in myocardial tissue when exposed to ultrasound of stated characteristics. The ultimate damage degree remains to be clarified.

Does low-energy ultrasound, known to enhance thrombolysis, affect the size of ischemic brain damage?

OBJECTIVE: In view of the potentially beneficial effects of ultrasound on fibrinolysis, we aimed to study possible drawbacks of low-energy ultrasound on nonperfused and perfused brain tissue. METHODS: A model of transient focal ischemia in anesthetized rats was used. Rats were randomly assigned to 1 of 3 groups: the first exposed to ultrasound, the second a control of the ultrasound group, and the third a method control group. In each group, the right middle cerebral artery was occluded for 1.5 hours, during which time the rats in the ultrasound group were exposed to 1 hour of pulsed ultrasound (1 MHz; spatial-average temporal-average intensity, 0.1 W/cm2 at a duty cycle of 10%). The occlusion period was followed by a 24-hour recirculation period, after which the brains were excised and evaluated. RESULTS: Ultrasound did not affect the volume of ischemic damage in nonperfused brain tissue or add ischemic damage to perfused brain tissue. CONCLUSIONS: Under these experimental conditions, ultrasound does not cause additional ischemic damage to the rat brain during middle cerebral artery occlusion.