Timothy Matsuura

Sodium nitroprusside enhanced cardiopulmonary resuscitation improves survival with good neurological function in a porcine model of prolonged cardiac arrest.

2261 Nighttime senior intensivist coverage is an important issue, discussed at the moment in many pediatric intensive care units (PICUs) worldwide. Therefore, studies on this topic are welcome. The specific local circumstances and organization of the PICU and the hospital dictate the optimal medical rosters. In this issue of Critical Care Medicine, Nishisaki et al (1) present their experiences with implementation of 24-hr in-hospital pediatric critical care attending coverage. The special features of their PICU are the following: no admissions of cardiac surgery patients and neonates after birth, low PICU mortality (2.2–2.5%), low proportion of ventilated patients, fairly high proportion of admissions after cardiopulmonary resuscitation on the floor (about 40 patients per year), and high proportion of admissions with malignancy. Senior consultant coverage during nighttime may be especially important in: 1) PICUs with postcardiac surgery patients because the nadir of cardiac function occurs typically 6–12 hrs after separation from cardiopulmonary bypass (2); 2) PICUs with admission of neonates directly after birth because childbirths happen to take place over night; and 3) PICUs with a high proportion of ventilated patients because of artificial ventilation–related complications. These risk factors are not present in the PICU described by Nishisaki et al (1). However, the PICU management of children after cardiac arrest on the ward may benefit from nighttime attendant presence. In a study from Australia, 20% of inhospital cardiac arrests were due to septic shock and 10% were due to upper airway obstruction (3). Because cardiac arrest is usually the culmination of prolonged hypoxemia or circulatory failure, there may be sufficient time to intervene and prevent it (3). Early detection of evolving, still compensated shock or respiratory failure is difficult and needs high clinical experience. Therefore, nighttime senior consultant coverage on the ward may be as important as in PICU. Too often, children need intensive care because of deficiencies in primary health care or care on general pediatric wards (4). Nishisaki et al (1) report on a significant decrease in PIUC length of stay and duration of mechanical ventilation. This fact alone is an important achievement because the duration of mechanical ventilation is associated with complications, such as ventilator associated pneumonia, sepsis, fluid overload and malnutrition, and renal failure. The authors claim that the shorter duration of mechanical ventilation and shorter length of stay are associated with the transition from a 12-hr to a 24-hr in-hospital pediatric critical care attending physician coverage model. I wonder whether this explanation is right or whether the authors should more cautiously state that there is just a significant improvement over time. For the standardized mortality ratio (SMR), calculated with Pediatric Index of Mortality 2 (5), many intensive care units observed an improvement over time and therefore are calling for a recalibration of the score (6). Obviously, intensive care units tend to improve with time. In our PICU in Zurich (around 1,300 admissions per year), we observed a steady improvement of the SMR, along with a decrease in the duration of intubation: mean duration of intubation (unfortunately, medians are not available any more): year 2000: 7.1 days, 2001: 6.6 days, 2002: 6.1 days, 2003: 5.3 days, 2004: 4.5 days, 2005: 5.6 days, 2006: 3.3 days, 2007: 2.6 days, 2008: 2.9 days, 2009: 2.8 days; SMR (95% confidence interval): 2004: 0.99 (0.75, 1.23), 2005: 1.27 (1.02, 1.52), 2006: 0.84 (0.59, 1.09), 2007: 0.74 (0.51, 0.97), 2008: 0.59 (0.36, 0.82), 2009: 0.53 (0.31, 0.75) (B. Frey, unpublished personal data). SMR is calculated from Pediatric Index of Mortality 2, which was released in 2003 (5). For the SMR, mean Pediatric Index of Mortality 2 values were used and the 95% confidence interval were calculated according to Rapoport et al (7). We had no major management changes such as the implementation of 24-hr in hospital attending coverage (in fact, consultants stay in hospital until 11 PM and thereafter are on call at home, obliged to return to the hospital within a maximum of 30 mins, if necessary). However, we had a multitude of subtle changes (improvements) over the last years, such as new guidelines, patient safety measures, improvements in resident/fellow/nursing teaching, strengthening of clinical pharmacy, and hospital hygiene. A further issue of nighttime attendant presence is related to fellow teaching. On one hand, there may be more bedside education provided at nighttime by attending physicians (1). On the other hand, fellows may be more tightly guided by their consultant; they may be less exposed to clinical problems, reducing their autonomy and decision-making skills. Education in intensive care medicine is a tightrope walk between direct supervision and autonomy of the fellow. In conclusion, it seems obvious that nighttime consultant presence improves quality and safety of care. The article by Nishisaki et al (1) adds at least some evidence to this assumption. It is difficult to argue that there is no need of experienced intensivists at the bedside of our sickest patients at night (i.e., half of a 24-hr day!).Objective: To assess the effectiveness of sodium nitroprusside (SNP)-“enhanced” cardiopulmonary resuscitation (SNPeCPR) on 24-hr survival rates compared to standard CPR in animals after cardiac arrest. SNPeCPR consists of large intravenous SNP bolus doses during CPR enhanced by active compression-decompression CPR, an inspiratory impedance threshold device (ITD), and abdominal binding (AB). The combination of active compression-decompression CPR+ITD+AB without SNP will be called “enhanced” or eCPR. Design: Randomized, blinded, animal study. Setting: Preclinical animal laboratory. Subjects: Twenty-four female farm pigs (30 ± 1 kg). Interventions: Isoflurane anesthetized and intubated pigs were randomized after 8 mins of untreated ventricular fibrillation to receive either standard CPR (n = 8), SNPeCPR (n = 8), or eCPR (n = 8) for 25 mins followed by defibrillation. Measurements and Main Results: The primary end point was carotid blood flow during CPR and 24-hr survival with good neurologic function defined as an overall performance category score of ≤2 (1 = normal, 5 = brain dead or dead). Secondary end points included hemodynamics and end-tidal CO2. SNPeCPR significantly improved carotid blood flow and 24-hr survival rates with good neurologic function compared to standard CPR or eCPR (six of eight vs. zero of eight vs. one of eight, p < .05). The improved survival rates were associated with higher coronary perfusion pressure and ETco2 during CPR. Conclusion: In pigs, SNPeCPR significantly improved hemodynamics, resuscitation rates, and 24-hr survival rates with good neurologic function after cardiac arrest when compared with standard CPR or eCPR alone.

Ischemic post-conditioning and vasodilator therapy during standard cardiopulmonary resuscitation to reduce cardiac and brain injury after prolonged untreated ventricular fibrillation

AIM OF THE STUDY We investigated the effects of ischemic postconditioning (IPC) with and without cardioprotective vasodilatory therapy (CVT) at the initiation of cardiopulmonary resuscitation (CPR) on cardio-cerebral function and 48-h survival. METHODS Prospective randomized animal study. Following 15 min of ventricular fibrillation, 42 Yorkshire farm pigs weighing an average of 34 ± 2 kg were randomized to receive standard CPR (SCPR, n=12), SCPR+IPC (n=10), SCPR+IPC+CVT (n=10), or SCPR+CVT (n=10). IPC was delivered during the first 3 min of CPR with 4 cycles of 20s of chest compressions followed by 20-s pauses. CVT consisted of intravenous sodium nitroprusside (2mg) and adenosine (24 mg) during the first minute of CPR. Epinephrine was given in all groups per standard protocol. A transthoracic echocardiogram was obtained on all survivors 1 and 4h post-ROSC. The brains were extracted after euthanasia at least 24h later to assess ischemic injury in 7 regions. Ischemic injury was graded on a 0-4 scale with (0=no injury to 4 ≥ 50% neural injury). The sum of the regional scores was reported as cerebral histological score (CHS). 48 h survival was reported. RESULTS Post-resuscitation left ventricular ejection (LVEF) fraction improved in SCPR+CVT, SCPR+IPC+CVT and SCPR+IPC groups compared to SCPR (59% ± 9%, 52% ± 14%, 52% ± 14% vs. 35% ± 11%, respectively, p<0.05). Only SCPR+IPC and SCPR+IPC+CVT, but not SCPR+CVT, had lower mean CHS compared to SCPR (5.8 ± 2.6, 2.8 ± 1.8 vs. 10 ± 2.1, respectively, p<0.01). The 48-h survival among SCPR+IPC, SCPR+CVT, SCPR+IPC+CVT and SCPR was 6/10, 3/10, 5/10 and 1/12, respectively (Cox regression p<0.01). CONCLUSIONS IPC and CVT during standard CPR improved post-resuscitation LVEF but only IPC was independently neuroprotective and improved 48-h survival after 15 min of untreated cardiac arrest in pigs.

Bundled postconditioning therapies improve hemodynamics and neurologic recovery after 17 min of untreated cardiac arrest

OBJECTIVE Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15min of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. METHODS Following 17min of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR+ITD+sevoflurane+P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. RESULTS Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48h), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48h). CONCLUSIONS Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17min of untreated cardiac arrest in pigs. All studies were performed with approval from the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation (protocol #12-11).

Tilting for perfusion: Head-up position during cardiopulmonary resuscitation improves brain flow in a porcine model of cardiac arrest

INTRODUCTION Cerebral perfusion is compromised during cardiopulmonary resuscitation (CPR). We hypothesized that beneficial effects of gravity on the venous circulation during CPR performed in the head-up tilt (HUT) position would improve cerebral perfusion compared with supine or head-down tilt (HDT). METHODS Twenty-two pigs were sedated, intubated, anesthetized, paralyzed and placed on a tilt table. After 6min of untreated ventricular fibrillation (VF) CPR was performed on 14 pigs for 3min with an automated CPR device called LUCAS (L) plus an impedance threshold device (ITD), followed by 5min of L-CPR+ITD at 0° supine, 5min at 30° HUT, and then 5min at 30° HDT. Microspheres were used to measure organ blood flow in 8 pigs. L-CPR+ITD was performed on 8 additional pigs at 0°, 20°, 30°, 40°, and 50° HUT. RESULTS Coronary perfusion pressure was 19±2mmHg at 0° vs. 30±3 at 30° HUT (p<0.001) and 10±3 at 30° HDT (p<0.001). Cerebral perfusion pressure was 19±3 at 0° vs. 35±3 at 30° HUT (p<0.001) and 4±4 at 30° HDT (p<0.001). Brain-blood flow was 0.19±0.04mlmin(-1)g(-1) at 0° vs. 0.27±0.04 at 30° HUT (p=0.01) and 0.14±0.06 at 30° HDT (p=0.16). Heart blood flow was not significantly different between interventions. With 0, 10, 20, 30, 40 and 50° HUT, ICP values were 21±2, 16±2, 10±2, 5±2, 0±2, -5±2 respectively, (p<0.001), CerPP increased linearly (p=0.001), and CPP remained constant. CONCLUSION During CPR, HDT decreased brain flow whereas HUT significantly lowered ICP and improved cerebral perfusion. Further studies are warranted to explore this new resuscitation concept.

Induction, maintenance, and reversal of therapeutic hypothermia with an esophageal heat transfer device

AIM OF THE STUDY To evaluate a novel esophageal heat transfer device for use in inducing, maintaining, and reversing hypothermia. We hypothesized that this device could successfully induce, maintain (within a 1 °C range of goal temperature), and reverse, mild therapeutic hypothermia in a large animal model over a 30-h treatment protocol. METHODS Five female Yorkshire swine, weighing a mean of 65 kg (range 61-70) kg each, were anesthetized with inhalational isoflurane via endotracheal intubation and instrumented. The esophageal device was connected to an external chiller and then placed into the esophagus and connected to wall suction. Reduction to goal temperature was achieved by setting the chiller to cooling mode, and a 24h cooling protocol was completed before rewarming and recovering the animals. Histopathologic analysis was scheduled for 3-14 days after protocol completion. RESULTS Average baseline temperature for the 5 animals was 38.6 °C (range 38.1-39.2 °C). All swine were cooled successfully, with average rate of temperature decrease of 1.3 °C/h (range 1.1-1.9) °C/h. Standard deviation from goal temperature averaged 0.2 °C throughout the steady-state maintenance phase, and no treatment for shivering was necessary during the protocol. Histopathology of esophageal tissue showed no adverse effects from the device. CONCLUSION A new esophageal heat transfer device successfully and safely induced, maintained, and reversed therapeutic hypothermia in large swine. Goal temperature was maintained within a narrow range, and thermogenic shivering did not occur. These findings suggest a useful new modality to induce therapeutic hypothermia.

Anaesthetic Postconditioning at the Initiation of CPR Improves Myocardial and Mitochondrial Function in a Pig Model of Prolonged Untreated Ventricular Fibrillation

BACKGROUND Anaesthetic postconditioning (APoC) attenuates myocardial injury following coronary ischaemia/reperfusion. We hypothesised that APoC at the initiation of cardiopulmonary resuscitation (CPR) will improve post resuscitation myocardial function along with improved mitochondrial function in a pig model of prolonged untreated ventricular fibrillation. METHODS In 32 pigs isoflurane anaesthesia was discontinued prior to induction of ventricular fibrillation that was left untreated for 15 min. At the initiation of CPR, 15 animals were randomised to controls (CON), and 17 to APoC with 2 vol% sevoflurane during the first 3 min CPR. Pigs were defibrillated after 4 min of CPR. After return of spontaneous circulation (ROSC), isoflurane was restarted at 0.8-1.5 vol% in both groups. Systolic and diastolic blood pressures were measured continuously. Of the animals that achieved ROSC, eight CON and eight APoC animals were randomised to have their left ventricular ejection fraction (LVEF%) assessed by echocardiography at 4h. Seven CON and nine APoC were randomised to euthanasia 15 min after ROSC to isolate mitochondria from the left ventricle for bioenergetic studies. RESULTS ROSC was achieved in 10/15 CON and 15/17 APoC animals. APoC improved haemodynamics during CPR and post-CPR LVEF%. Mitochondrial ATP synthesis, coupling of oxidative phosphorylation and calcium retention capacity were improved in cardiac mitochondria isolated after APoC. CONCLUSIONS In a porcine model of prolonged untreated cardiac arrest, APoC with inhaled sevoflurane at the initiation of CPR, is associated with preserved mitochondrial function and improved post resuscitation myocardial dysfunction. Approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation of Hennepin County Medical Center (protocol number 11-05).

Post-conditioning to improve cardiopulmonary resuscitation

Purpose of reviewDespite decades of advances in prehospital and in-hospital medical care, patients with out-of-hospital cardiac arrest continue to have poor neurologic and cardiac function following otherwise successful resuscitation. This review examines the mechanisms and therapeutic strategies currently under development to activate the post-conditioning pathways and thereby improve survival and function. Recent findingsPost-conditioning utilizes the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways as common avenues to promote cell survival and function. Ischemic post-conditioning and multiple medications activate these pathways resulting in improved cardiac and neurological function in animal models of cardiac arrest. SummaryDetailed knowledge of the RISK and SAFE pathways can be used for further drug development. Human studies are now underway to test some of these strategies, but further clinical trials are necessary to translate these therapies to clinical practice.

Intrathoracic Pressure Regulation Improves Cerebral Perfusion and Cerebral Blood Flow in a Porcine Model of Brain Injury.

ABSTRACT Brain injury is a leading cause of death and disability in children and adults in their most productive years. Use of intrathoracic pressure regulation (IPR) to generate negative intrathoracic pressure during the expiratory phase of positive pressure ventilation improves mean arterial pressure and 24-h survival in porcine models of hemorrhagic shock and cardiac arrest and has been demonstrated to decrease intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these models. Application of IPR for 240 min in a porcine model of intracranial hypertension (ICH) will increase CPP when compared with controls. Twenty-three female pigs were subjected to focal brain injury by insertion of an epidural Foley catheter inflated with 3 mL of saline. Animals were randomized to treatment for 240 min with IPR set to a negative expiratory phase pressure of −12 cmH2O or no IPR therapy. Intracranial pressure, mean arterial pressure, CPP, and cerebral blood flow (CBF) were evaluated. Intrathoracic pressure regulation significantly improved mean CPP and CBF. Specifically, mean CPP after 90, 120, 180, and 240 min of IPR use was 43.7 ± 2.8 mmHg, 44.0 ± 2.7 mmHg, 44.5 ± 2.8 mmHg, and 43.1 ± 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 ± 1.7 mmHg) compared with control animals in which mean CPP was 36.7 ± 1.4 mmHg (ICH study baseline) and then 35.9 ± 2.1 mmHg, 33.7 ± 2.8 mmHg, 33.9 ± 3.0 mmHg, and 36.0 ± 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P < 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 ± 4 mL/100 g-min to 49 ± 7 mL/100 g-min at 90 min) but not in controls (27 ± 1 mL/100 g-min to 25 ± 5 mL/100 g-min at 90 min) (P = 0.01). Arterial pH remained unchanged during the entire period of IPR compared with baseline values and control values. In this anesthetized pig model of ICH, treatment with IPR significantly improved CPP and CBF. This therapy may be of clinical value by noninvasively improving cerebral perfusion in states of compromised cerebral perfusion.

Sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-arrest therapeutic hypothermia in a porcine model of prolonged ventricular fibrillation.

Objectives:The aim of this study was to assess the effect of sodium nitroprusside–enhanced cardiopulmonary resuscitation on heat exchange during surface cooling. We hypothesized that sodium nitroprusside–enhanced cardiopulmonary resuscitation would decrease the time required to reach brain temperature less than 35°C compared to active compression-decompression plus impedance threshold device cardiopulmonary resuscitation alone, in the setting of intra–cardiopulmonary resuscitation cooling. We further hypothesized that the addition of epinephrine during sodium nitroprusside–enhanced cardiopulmonary resuscitation would mitigate heat exchange. Design:Prospective randomized animal investigation. Setting:Preclinical animal laboratory. Subjects:Female farm pigs (n = 28). Interventions:After 10 minutes of untreated ventricular fibrillation, animals were randomized to three different protocols: sodium nitroprusside–enhanced cardiopulmonary resuscitation (n = 8), sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine (n = 10), and active compression-decompression plus impedance threshold device alone (control, n = 10). All animals received surface cooling at the initiation of cardiopulmonary resuscitation. Sodium nitroprusside–enhanced cardiopulmonary resuscitation included active compression-decompression plus impedance threshold device plus abdominal binding and 2 mg of sodium nitroprusside at 1, 4, and 8 minutes of cardiopulmonary resuscitation. No epinephrine was used during cardiopulmonary resuscitation in the sodium nitroprusside–enhanced cardiopulmonary resuscitation group. Control and sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine groups received 0.5 mg of epinephrine at 4.5 and 9 minutes of cardiopulmonary resuscitation. Defibrillation occurred after 10 minutes of cardiopulmonary resuscitation. After return of spontaneous circulation, an Arctic Sun (Medivance, Louiseville, CO) was applied at maximum cooling on all animals. The primary endpoint was the time required to reach brain temperature less than 35°C beginning from the time of cardiopulmonary resuscitation initiation. Data are presented as mean ± SEM. Measurements and Main Results:The time required to reach a brain temperature of 35°C was decreased with sodium nitroprusside–enhanced cardiopulmonary resuscitation versus control or sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine (24 ± 6 min, 63 ± 8 min, and 50 ± 9 min, respectively; p = 0.005). Carotid blood flow was higher during cardiopulmonary resuscitation in the sodium nitroprusside–enhanced cardiopulmonary resuscitation group (83 ± 15 mL/min vs 26 ± 7 mL/min and 35 ± 5 mL/min in the control and sodium nitroprusside–enhanced cardiopulmonary resuscitation plus epinephrine groups, respectively; p = 0.001). Conclusions:This study demonstrates that sodium nitroprusside–enhanced cardiopulmonary resuscitation facilitates intra–cardiopulmonary resuscitation hypothermia. The addition of epinephrine to sodium nitroprusside–enhanced cardiopulmonary resuscitation during cardiopulmonary resuscitation reduced its improvement in heat exchange.

Fluidless resuscitation with permissive hypotension via impedance threshold device therapy compared with normal saline resuscitation in a porcine model of severe hemorrhage.

BACKGROUND One approach to improve outcomes after trauma and hemorrhage is to follow the principles of permissive hypotension by avoiding intravascular overpressure and thereby preventing dislodgement of platelet plugs early in the clotting process. We hypothesized that augmentation of negative intrathoracic pressure (nITP) by treatment with an impedance threshold device would improve hemodynamics without compromising permissive hypotension or causing hemodilution, whereas aggressive fluid resuscitation with normal saline (NS) would result in hemodilution and SBPs that are too high for permissive hypotension and capable of clot dislodgement. METHODS Thirty-four spontaneously breathing anesthetized female pigs (30.6 ± 0.5 kg) were subjected to a fixed 55% hemorrhage over 30 minutes; block randomized to nITP, no treatment, or intravenous bolus of 1-L NS; and evaluated over 30 minutes. Results are reported as mean ± SEM. RESULTS Average systolic blood pressures (SBPs) (mm Hg) 30 minutes after the study interventions were as follows: nITP, 82.1 ± 2.9; no treatment, 69.4 ± 4.0; NS 89.3 ± 5.2. Maximum SBPs during the initial 15 minutes of treatment were as follows: nITP, 88.0 ± 4.3; no treatment, 70.8 ± 4.3; and NS, 131 ± 7.6. After 30 minutes, mean pulse pressure (mm Hg) was significantly higher in the nITP group (nITP, 32.3 ± 2.2) versus the no-treatment group (21.5 ± 1.5 controls) (p < 0.05), and the mean hematocrit was 25.2 ± 0.8 in the nITP group versus 19 ± 0.6 in the NS group (p < 0.001). CONCLUSION In this porcine model of hemorrhagic shock, nITP therapy significantly improved SBP and pulse pressure for 30 minutes without overcompensation compared with controls with no treatment. By contrast, aggressive fluid resuscitation with NS but not nITP resulted in a significant rise in SBP to more than 100 mm Hg within minutes of initiating therapy that could cause a further reduction in hematocrit and clot dislodgment.