Laurence M. Katz

Outcome Model of Asphyxial Cardiac Arrest in Rats

An outcome model with asphyxial cardiac arrest in rats has been developed for quantifying brain damage. Twenty-two rats were randomized into three groups. Control group I was normal, was conscious, and had no asphyxia (n = 6). Sham group II had anesthesia and surgery but no asphyxia (n = 6). All 12 rats in groups I and II survived to 72 h and were functionally and histologically normal. Arrest group III (the model; n = 10) had light anesthesia and apneic asphyxia of 8 min, which led to cessation of circulation at 3–4 min of apnea, resulting in cardiac arrest (no flow) of 4–5 min. All 10 rats had spontaneous circulation restored by standard external cardiopulmonary resuscitation. Nine rats survived controlled ventilation for 1 h and observation to 72 h, while one rat died before extubation. All nine survivors were conscious at 72 h, with neurologic deficit scores (0% = best; 100% = worst) of 7 ± 69? (2–16%). All brain regions at five coronal levels were examined for ischemic neurons. The prevalence of ischemic neurons in five regions was categorically scored. The average total brain histopathologic damage score in group III (n = 9) was 2.1 (p < 0.05 vs. group I or II). A reproducible outcome model of cardiac arrest in rats was documented. It provides a tool for investigating pathophysiological mechanisms of neuronal death caused by a transient global hypoxic–ischemic brain insult.

Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats

Although high-dose epinephrine during CPR improves coronary perfusion pressure (CoPP) and rate of return of spontaneous circulation (ROSC) in some models, its impact on long term outcome (> or = 72 h) has not been evaluated. Previous studies of sodium bicarbonate (NaHCO3) therapy during CPR indicate that beneficial effects may be dependent on epinephrine (EPI) dose. We hypothesized that EPI and NaHCO3 given during CPR have a significant impact on long term outcome. One hundred male Sprague-Dawley rats were prospectively studied in a block randomized placebo controlled trial. Rats were anesthetized, paralyzed, mechanically ventilated, instrumented, and each underwent 10 min of asphyxia, resulting in 6.8 +/- 0.4 min of circulatory arrest. Resuscitation was performed by mechanical ventilation and manual external chest compressions. EPI 0.0 (placebo), 0.01, 0.1, or 1.0 mg/kg IV was given at the onset of CPR, followed by NaHCO3 0.0 (placebo) or 1.0 mEq/kg IV. Successfully resuscitated rats were monitored and ventilated for 1 h without hemodynamic support. Neurologic deficit scores (NDS), cerebral histopathologic damage scores (CHDS) and myocardial histopathologic damage scores (MHDS) were determined in rats that survived 72 h. EPI improved CoPP and ROSC in a dose-dependent manner up to 0.1 mg/kg. Rats receiving EPI 0.1 and 1.0 mg/kg during CPR exhibited prolonged post-ROSC hypertension and metabolic acidemia, increased A-a O2 gradient, and an increased incidence of post-ROSC ventricular tachycardia or fibrillation. Overall survival was lower with EPI 0.1 and 1.0 mg/kg compared to 0.01 mg/kg. Although NDS was significantly less with EPI 0.1 mg/kg compared to placebo, there was no difference in CHDS between groups. In contrast, MDS was significantly higher with EPI 0.1 mg/kg compared to placebo or EPI 0.01 mg/kg. There was an overall trend toward improved survival at 72 h in rats that received NaHCO3 which was most evident in the EPI 0.1 mg/kg group. We conclude that (1) EPI during CPR has a biphasic dose/response curve in terms of survival, when post-resuscitation effects are left untreated and (2) NaHCO3 doses greater than 1.0 mEq/kg may be necessary to treat the side-effects of high-dose EPI. Further work is needed to determine if treating the immediate post-resuscitation effects of high-dose EPI can prevent detrimental effects on long-term outcome.

Aerobic fitness and obesity: relationship to cerebral white matter integrity in the brain of active and sedentary older adults

Objective Aerobic fitness (VO2 peak) and obesity risk (OR) may impact brain health. This study examined hemispheric and segment specific relationships between VO2 peak, OR and cerebral white-matter (CWM) integrity in the cingulum brain region in healthy older adults. Methods Fifteen subjects (66±6 years) completed VO2 peak testing and MRI of the brain. OR was determined via body mass index (BMI) and abdominal girth. MRI analysis was performed with a structural 3D T1 MP-Rage and diffusion tensor imaging technique (DTI, 21 directions, repeated four times) on a 3.0 T MR imaging unit. CWM integrity indices, fractional anisotropy (FA) and mean diffusivity (MD), were computed from the tensors. The anterior, middle and posterior cingulum segments were analysed on both sides of the brain. Partial correlations (age and gender controlled) and standard multiple regressions were used to determine significant associations and unique contributions to CWM integrity. Results VO2 peak was moderately related to FA in the left middle cingulum segment (r partial=0.573, p=0.041) and explained 28.5% of FAs total variance (p=0.10). Abdominal girth (r partial=−0.764, p=0.002) and BMI (r partial=−0.690, p=0.009) were inversely related to FA in the right posterior cingulum (RPC) segment. Abdominal girth and BMI uniquely explained 53.9% of FAs total variance (p=0.012) and 43.9% (p=0.040), respectively, in the RPC. Conclusion Higher aerobic fitness and lower obesity risk are related to greater CWM integrity but not in the same cingulum segments.

Bovine hemoglobin-based oxygen carrier (HBOC-201) for resuscitation of uncontrolled, exsanguinating liver injury in swine

In the setting of rapidly exsanguinating hemorrhage, resuscitation with intravenous (i.v.) crystalloid solution may not sustain survival before availability of allogenic blood transfusion and surgery. This study tested the hypothesis that bovine hemoglobin-based oxygen carrier, HBOC-201, would improve resuscitation and extend early survival from exsanguinating hemorrhage. This study simulated the prehospital scenario of rapidly exsanguinating hemorrhage with prolonged prehospital time and lack of blood availability. Severe hemorrhagic shock was induced in swine by using multiple liver lacerations. At 9 min after the onset of bleeding, swine were randomized to receive approximately 10 mL/kg/min of i.v. lactated Ringers solution (n = 10) or HBOC-201 (n = 7) to achieve a mean aortic pressure (MAP) of 60 mmHg. Thereafter, infusion rate was adjusted to maintain MAP at 60 mmHg for up to 2 h. All animals were initially successfully resuscitated. The results showed 2-h survival was 1 of 10 with lactated Ringers and 7 of 7 with HBOC-201 (P = 0.0004). Nine lactated Ringers swine had cardiovascular collapse at 36 +/- 10 min. Lactate at 30 min was 18 +/- 3 mmol/L with lactated Ringers and 12 +/- 2 mmol/L with HBOC-201 (P < 0.05). Hematocrit was <1% in 9 of 10 lactated Ringers and 6 of 7 HBOC-201 animals. These data indicate that HBOC-201 improved early survival and stabilized hemodynamic and metabolic parameters vs. lactated Ringers in this swine model of liver injury with uncontrolled, lethal hemorrhage that simulates the prehospital care environment where allogenic blood is unavailable.

The Effect of Exercise on the Cerebral Vasculature of Healthy Aged Subjects as Visualized by MR Angiography

BACKGROUND AND PURPOSE: Prior studies suggest that aerobic exercise may reduce both the brain atrophy and the decline in fractional anisotropy observed with advancing age. It is reasonable to hypothesize that exercise-induced changes to the vasculature may underlie these anatomic differences. The purpose of this blinded study was to compare high-activity and low-activity healthy elderly volunteers for differences in the cerebrovasculature as calculated from vessels extracted from noninvasive MR angiograms (MRAs). MATERIALS AND METHODS: Fourteen healthy elderly subjects underwent MRA. Seven subjects reported a high level of aerobic activity (64 ± 5 years of age; 5 men, 2 women) and 7, a low activity level (68 ± 6 years of age; 5 women, 2 men). Following vessel segmentation from MRA by an individual blinded to subject activity level, quantitative measures of vessel number, radius, and tortuosity were calculated and histogram analysis of vessel number and radius was performed. RESULTS: Aerobically active subjects exhibited statistically significant reductions in vessel tortuosity and an increased number of small vessels compared with less active subjects. CONCLUSIONS: Aerobic activity in elderly subjects is associated with lower vessel tortuosity values and an increase in the number of small-caliber vessels. It is possible that an aerobic exercise program may contribute to healthy brain aging. MRA offers a noninvasive approach to visualizing the cerebral vasculature and may prove useful in future longitudinal investigations.

Feasibility of external cranial cooling during out-of-hospital cardiac arrest

Hypothermia during brain ischemia can improve neurological outcome. This study tested whether local cranial cooling during the low-flow state of cardiopulmonary resuscitation (CPR) could produce clinically significant cerebral cooling. Ice was applied to the heads and necks of subjects (hypothermia group) with out-of-hospital cardiac arrest (OOHCA) during CPR. Nasopharyngeal and tympanic temperatures were measured as surrogates for cerebral temperature. The rate of cranial cooling in the hypothermia group (-0.06 +/- 0.06 degrees C/min) was not significantly increased compared with a control group without ice (-0.04 +/- 0.07 degrees C/min), although older age was associated with more rapid cranial cooling. Of note, many subjects with OOHCA are already mildly hypothermic (mean cranial temperature= 35.0 +/- 1.2 degrees C) when they are first encountered in the field. This study suggests that brief cranial cooling is ineffective for rapidly lowering brain temperature. However, most cardiac arrest victims are spontaneously mildly hypothermic and preventing rewarming may provide some of the desired benefits of cerebral hypothermia.

Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia

ObjectiveExternal cooling is commonly used to force induction of mild hypothermia but requires equipment, has a slow onset of action, and must be prolonged to provide permanent neurologic benefits after hypoxic-ischemia. It is unknown whether the method for inducing mild hypothermia affects neurologic outcome after near-drowning. The objective of the study was to induce mild hypothermia with neurotensin analog NT77 or external cooling in a rat model of near-drowning. We hypothesize that NT77 would be more effective for improving neurologic outcome than external cooling of the same duration. DesignRats were randomized to a normothermic control, neurotensin-induced hypothermia, brief external cooling, or prolonged external cooling group after asphyxial cardiac arrest. SettingLaboratory investigation. SubjectsForty-eight rats. InterventionsMild hypothermia was induced by external cooling for 4 hrs (brief external cooling) or 24 hrs (prolonged external cooling) or by neurotensin-induced hypothermia administration 30 mins after asphyxial cardiac arrest in rats. MeasurementsOutcome was assessed by a neurologic deficit score, the Morris water maze, and CA1 hippocampus histology 15 days after resuscitation. Main ResultsNeurologic deficit score at 72 hrs after asphyxial cardiac arrest was lower with neurotensin-induced hypothermia (score, 0) and prolonged external cooling (score, 0) vs. normothermic control (score, 20) and brief external cooling (score, 18; p < .05). Latency time in the Morris water maze 15 days after asphyxial cardiac arrest was decreased with neurotensin-induced hypothermia (14 ± 11 secs) and prolonged external cooling (18 ± 9 secs) vs. normothermic control (74 ± 17 secs) and brief external cooling (78 ± 18 secs, p < .05). There was less ischemic neuronal damage with neurotensin-induced hypothermia (28 ± 24%) and prolonged external cooling (21 ± 14%) vs. normothermic control (61 ± 32%) and brief external cooling (51 ± 32%). ConclusionsNeurotensin-induced hypothermia improved neurologic outcome after asphyxial cardiac arrest in rats vs. brief external cooling but was comparable to prolonged external cooling.

Regulated hypothermia reduces brain oxidative stress after hypoxic-ischemia.

UNLABELLED Regulated hypothermia produces a decrease in core temperature by lowering the brains temperature set-point while maintaining thermoregulation at that lower set point. In contrast, forced hypothermia lowers core temperature by overwhelming the bodys capacity to thermoregulate, but does not change the set-point. Regulated hypothermia has been shown to be cerebral protective in hibernating mammals. The effect of regulated hypothermia on the brain during reperfusion from hypoxic-ischemia has not been well studied. We induced regulated hypothermia with a neurotensin analogue (NT77) to determine whether it could reduce oxidative stress in the brain during reperfusion from asphyxial cardiac arrest (ACA) in rats. Mild hypothermia (32-34 degrees C) was induced by brief (4 h) external cooling (BC), NT77 or prolonged external cooling (24 h) (PC) 30 min after resuscitation from 8 min of ACA in rats. Malondialdehyde (MDA) levels in the brain were measured during reperfusion to quantitate oxidative stress. RESULTS MDA levels in the hippocampus were elevated at 16 h of normothermic reperfusion versus 48 h with BC reperfusion. There was no increase in hippocampal MDA levels in the NT77 and PC groups at 24-72 h of reperfusion. Regulated hypothermia induced by NT77 reduced oxidative stress in the hippocampus during reperfusion from hypoxic-ischemia in comparison to forced brief external cooling of the same duration. In addition, the duration of external cooling after resuscitation also alters oxidative stress in the brain during reperfusion.

Glucose plus insulin infusion improves cerebral outcome after asphyxial cardiac arrest

HYPERGLYCEMIA before ischemia worsens cerebral outcome. The aim of this study was to determine the cerebral effects of giving glucose with or without insulin after asphyxial cardiac arrest. Rats underwent 8 min of asphyxial cardiac arrest. After arrest, Group 1 received NaCl; Group 2, insulin; Group 3, glucose; and Group 4, glucose plus insulin, all intravenously. Neurological deficit (ND) scores were 14 ± 10%, 22 ± 12%, 12 ± 10% and 2 ± 2% in Groups 1–4, respectively, 72 h after reperfusion. Overall histological damage (HD) scores were 4, 2, 3 and 1, respectively. Group 4 fared significantly better than group 1 on both scores. Glucose after asphyxial cardiac arrest in rats produces no increased brain damage while glucose plus insulin improves cerebral outcome.

HBOC-201 improves survival in a swine model of hemorrhagic shock and liver injury

BACKGROUND Blunt abdominal trauma that leads to hemorrhagic shock and cardiac arrest is almost always fatal in the prehospital setting. The current study investigated whether a hemoglobin-based oxygen carrier (HBOC-201) could maintain organ viability during an exsanguinating liver injury and allow for prolonged survival. This hypothesis was tested in a large animal model that simulated blunt abdominal trauma with major organ injury. METHODS Swine underwent a liver crush, laceration and 50 ml/kg initial blood loss. The liver bled at 3 ml/kg per min during the resuscitation phase. No fluid (NF=6), hetastarch (HES=8), or HBOC-201 (HBOC=8) was given during the resuscitation phase. Swine alive 60 min after the initial injury underwent liver repair and 96 h observation. RESULTS All HBOC swine survived 60 min versus none of the NF or HES swine (P<0.05). All HBOC swine survived 24 h and 7/8 survived 96 h with good functional recovery. CONCLUSIONS HBOC resuscitation during liver bleeding in a swine model of hemorrhagic shock and liver injury allowed for 96 h survival. No fluid or HES in the same model was fatal.