Effect of mild hypothermia on cerebral oxygen uptake during gradual cerebral perfusion pressure decrease in piglets

OBJECTIVE: To study the effect of mild hypothermia on cerebral oxygen metabolism and brain function in piglets during reduced cerebral blood flow because of gradual reduction of the effective cerebral perfusion pressure (CPP). DESIGN: Comparison of two randomized treatment groups: normothermic group (NT; n = 7) and hypothermic group (HT; n = 7). SETTING: Work was conducted in the research laboratory of the Institute for Pathophysiology, Friedrich Schiller University, Jena, Germany. SUBJECTS: Fourteen piglets (14 days old) of mixed German domestic breed. INTERVENTION: Animals were anesthetized and mechanically ventilated. An epidural balloon was gradually inflated to increase intracranial pressure to 25 mm Hg, 35 mm Hg, and 45 mm Hg every 30 mins at adjusted mean arterial blood pressures. After determination of baseline CPP (NT, 79+/-14 mm Hg; HT, 84+/-9 mm Hg), CPP was reduced to approximately 70%, 50%, and 30% of baseline (NT, 38.1+/-0.5 degrees C; HT, 31.7+/-0.5 degrees C). MEASUREMENTS AND Main RESULTS: Every 25 mins after the gradual CPP reductions. Mild hypothermia induced a reduction of the cerebral metabolic rate of oxygen (CMRO2) to 50%+/-15% of baseline values (baseline values, 352+/-99 micromol x 100 g(-1) x min(-1)) (p < .05). Moreover, the electrocorticogram was altered to a pattern of reduced delta activity (p < .05) but unchanged higher frequency activity. The cerebral oxygen balance in HT animals remained improved until CPP reduction to 50%, indicated by a reduced cerebral arteriovenous difference of oxygen but elevated brain tissue Po2 (p < .05). Further CPP reduction gave rise to a strong CMRO2 reduction (NT, 19+/-21%; HT, 15+/-15%; p < .05). However, the high-frequency band of electrocorticogram was less reduced in hypothermic animals (p < .05). CONCLUSIONS: Mild whole body hypothermia improves cerebral oxygen balance by reduction of brain energy demand in juvenile piglets. The improvement of brain oxygen availability continues during a mild to moderate CPP decrease. A loss of the difference in CMRO2 between the hypothermic and normothermic piglets together with the fact that brain electrical activity was less suppressed under hypothermia during severe cerebral blood flow reduction indicates that hypothermic protection may involve some other mechanisms than reduction of brain oxidative metabolism.     

Comparison of a 10-breaths-per-minute versus a 2-breaths-per-minute strategy during cardiopulmonary resuscitation in a porcine model of cardiac arrest

BACKGROUND: Hyperventilation during cardiopulmonary resuscitation (CPR) is harmful. METHODS: We tested the hypotheses that, during CPR, 2 breaths/min would result in higher cerebral perfusion pressure and brain-tissue oxygen tension than 10 breaths/min, and an impedance threshold device (known to increase circulation) would further enhance cerebral perfusion and brain-tissue oxygen tension, especially with 2 breaths/min. RESULTS: Female pigs (30.4 +/- 1.3 kg) anesthetized with propofol were subjected to 6 min of untreated ventricular fibrillation, followed by 5 min of CPR (100 compressions/min, compression depth of 25% of the anterior-posterior chest diameter), and ventilated with either 10 breaths/min or 2 breaths/min, while receiving 100% oxygen and a tidal volume of 12 mL/kg. Brain-tissue oxygen tension was measured with a probe in the parietal lobe. The impedance threshold device was then used during an 5 additional min of CPR. During CPR the mean +/- SD calculated coronary and cerebral perfusion pressures with 10 breaths/min versus 2 breaths/min, respectively, were 17.6 +/- 9.3 mm Hg versus 14.3 +/- 6.5 mm Hg (p = 0.20) and 16.0 +/- 9.5 mm Hg versus 9.3 +/- 12.5 mm Hg (p = 0.25). Carotid artery blood flow, which was prospectively designated as the primary end point, was 65.0 +/- 49.6 mL/min in the 10-breaths/min group, versus 34.0 +/- 17.1 mL/min in the 2-breaths/min group (p = 0.037). Brain-tissue oxygen tension was 3.0 +/- 3.3 mm Hg in the 10-breaths/min group, versus 0.5 +/- 0.5 mm Hg in the 2-breaths/min group (p = 0.036). After 5 min of CPR there were no significant differences in arterial pH, PO2, or PCO2 between the groups. During CPR with the impedance threshold device, the mean carotid blood flow and brain-tissue oxygen tension in the 10-breaths/min group and the 2-breaths/min group, respectively, were 102.5 +/- 67.9 mm Hg versus 38.8 +/- 23.7 mm Hg (p = 0.006) and 4.5 +/- 6.0 mm Hg versus 0.7 +/- 0.7 mm Hg (p = 0.032). CONCLUSIONS: Contrary to our initial hypothesis, during the first 5 min of CPR, 2 breaths/min resulted in significantly lower carotid blood flow and brain-tissue oxygen tension than did 10 breaths/min. Subsequent addition of an impedance threshold device significantly enhanced carotid flow and brain-tissue oxygen tension, especially in the 10-breaths/min group.     

Prone position in subarachnoid hemorrhage patients with acute respiratory distress syndrome: effects on cerebral tissue oxygenation and intracranial pressure

OBJECTIVE: To analyze the effect of prone position on cerebral perfusion pressure and brain tissue oxygen partial pressure in subarachnoid hemorrhage patients with acute respiratory distress syndrome (ARDS). DESIGN: Clinical study with retrospective data analysis. SETTING: Neurosurgical intensive care unit of a primary level university hospital. PATIENTS: Sixteen patients treated for intracranial aneurysm rupture with initial Hunt and Hess grade III or worse who developed ARDS within 2 wks after the bleeding. INTERVENTIONS: Routine neurosurgical intensive care treatment for subarachnoid hemorrhage and posthemorrhagic vasospasm including cerebral monitoring with continuous intracranial pressure and brain tissue oxygen partial pressure recordings. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, arterial oxygenation, ventilatory setting, intracranial pressure, cerebral perfusion pressure, and brain tissue oxygen partial pressure in the supine as well as in the prone position were analyzed and compared. A significant increase in Pao(2) from 97.3 +/- 20.7 torr (mean +/- sd) in the supine position to 126.6 +/- 31.7 torr in the prone position was joined by a significant increase in brain tissue oxygen partial pressure from 26.8 +/- 10.9 torr to 31.6 +/- 12.2 torr (both p <.0001), whereas intracranial pressure increased from 9.3 +/- 5.2 mm Hg to 14.8 +/- 6.7 mm Hg and cerebral perfusion pressure decreased from 73.0 +/- 10.5 mm Hg to 67.7 +/- 10.7 mm Hg (both p <.0001). CONCLUSIONS: The beneficial effect of prone positioning on cerebral tissue oxygenation by increasing arterial oxygenation appears to outweigh the expected adverse effect of prone positioning on cerebral tissue oxygenation by decreasing cerebral perfusion pressure in ARDS patients.     

Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury

OBJECTIVE: In this study we have used O positron emission tomography, brain tissue oxygen monitoring, and cerebral microdialysis to assess the effects of cerebral perfusion pressure augmentation on regional physiology and metabolism in the setting of traumatic brain injury. DESIGN: Prospective interventional study. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven acutely head-injured patients requiring norepinephrine to maintain cerebral perfusion pressure. INTERVENTIONS: Using positron emission tomography, we have quantified the response to an increase in cerebral perfusion pressure in a region of interest around a brain tissue oxygen sensor (Neurotrend) and microdialysis catheter. Oxygen extraction fraction and cerebral blood flow were measured with positron emission tomography at a cerebral perfusion pressure of approximately 70 mm Hg and approximately 90 mm Hg using norepinephrine to control cerebral perfusion pressure. All other aspects of physiology were kept stable. MEASUREMENTS AND MAIN RESULTS: Cerebral perfusion pressure augmentation resulted in a significant increase in brain tissue oxygen (17 +/- 8 vs. 22 +/- 8 mm Hg; 2.2 +/- 1.0 vs. 2.9 +/- 1.0 kPa, p < .001) and cerebral blood flow (27.5 +/- 5.1 vs. 29.7 +/- 6.0 mL/100 mL/min, p < .05) and a significant decrease in oxygen extraction fraction (33.4 +/- 5.9 vs. 30.3 +/- 4.6 %, p < .05). There were no significant changes in any of the microdialysis variables (glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol). There was a significant linear relationship between brain tissue oxygen and oxygen extraction fraction (r = .21, p < .05); the brain tissue oxygen value associated with an oxygen extraction fraction of 40% (the mean value for oxygen extraction fraction in normal controls) was 14 mm Hg (1.8 kPa). The cerebral perfusion pressure intervention resulted in a greater percentage increase in brain tissue oxygen than the percentage decrease in oxygen extraction fraction; this suggests that the oxygen gradients between the vascular and tissue compartments were reduced by the cerebral perfusion pressure intervention. CONCLUSIONS: Cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry. Our results suggest that the ischemic level of brain tissue oxygen may lie at a level below 14 mm Hg (1.8 kPa); however, the data do not allow us to be more specific.     

Sufentanil, fentanyl, and alfentanil in head trauma patients: a study on cerebral hemodynamics

OBJECTIVES: To determine the effects of bolus injection and infusion of sufentanil, alfentanil, and fentanyl on cerebral hemodynamics and electroencephalogram activity in patients with increased intracranial pressure (ICP) after severe head trauma. DESIGN: Randomized, unblended, crossover study. SETTING: Intensive care unit and trauma center in a university hospital. PATIENTS: Six patients with head trauma and ICP monitoring, sedated at the time of the study with propofol infusion and full neuromuscular blockade. INTERVENTIONS: Following a randomized order, in an unblended and crossover fashion, the level of sedation was deepened with a 6-min injection of either sufentanil (1 microg/kg), alfentanil (100 microg/kg), or fentanyl (10 microg/kg) followed by an infusion of 0.005, 0.7, and 0.075 microg/kg/min, respectively, for 1 hr. The three opioids were given to each patient at 24-hr intervals. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure (MAP), ICP, cerebral perfusion pressure (CPP), and jugular vein bulb oxygen saturation (Svjo2) were continuously measured and recorded at 1-min intervals throughout the 60-min study period. Sufentanil, fentanyl, and alfentanil infusions were associated with a significant but transient increase in ICP (9+/-2 mm Hg [SD], 8+/-2 mm Hg, and 5.5+/-1 mm Hg, respectively; p<.05). The increase in ICP peaked at 5, 6, and 3 mins, respectively, then gradually decreased and returned to baseline values after 15 mins. This result was accompanied by a significant decrease in MAP (21+/-2 mm Hg, 24+/-2 mm Hg, and 26+/-2 mm Hg, respectively; p<.05) and, thus, in CPP (30+/-3 mm Hg, 31+/-3 mm Hg, and 34+/-3 mm Hg, respectively; p<.05). After 5 mins, MAP and CPP gradually increased, although they remained significantly decreased throughout the study period. No changes in lactate-oxygen index, used as an ischemia index, were observed. Changes in electroencephalogram tracings were characterized by a switch from a fast to a decreased activity, together with an improvement in the background activity. CONCLUSION: The results of the present study show that alfentanil, sufentanil, and fentanyl produce similar transient increases in ICP when administered by bolus injection in patients with increased ICP. No evidence of cerebral ischemia was observed in the study patients.     

Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients

OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.     

Effects of hyperbaric treatment in cerebral air embolism on intracranial pressure, brain oxygenation, and brain glucose metabolism in the pig

OBJECTIVE: To evaluate the effects of hyperbaric oxygen treatment after cerebral air embolism on intracranial pressure, brain oxygenation, brain glucose/lactate metabolism, and electroencephalograph. DESIGN: Prospective animal study. SETTING: Hyperbaric chamber. SUBJECTS: Eleven Landrace/Yorkshire pigs. INTERVENTIONS: In 11 anesthetized pigs, intracranial pressure and brain oxygenation were measured with microsensor technology, brain glucose/lactate by microdialysis, and electroencephalograph by conventional methods. After injection of air into the internal carotid artery, animals were treated immediately (at 3 mins; t = 3) or at 60 mins (t = 60) with U.S. Navy Treatment Table 6 for 4.48 hrs. RESULTS: At the end of hyperbaric oxygen treatment, intracranial pressure in the t = 60 group (39 +/- 8 mm Hg) was significantly higher than in the t = 3 group (27 +/- 6 mm Hg), brain oxygenation values for group t = 3 and t = 60 were 66 +/- 14 and 52 +/- 15 mm Hg, respectively (no significant difference from baseline), and there were no pathologic scores in the visually assessed electroencephalograph. However, there was a significant decrease in brain glucose and a significant increase in brain lactate in both groups at the end of the 5-hr study period. CONCLUSIONS: Hyperbaric oxygen treatment initiated at both 3 and 60 mins after embolization decreased the deleterious effects of cerebral air embolism on intracranial pressure and brain metabolism. Therefore, this model appears suitable to test the application of hyperbaric oxygen treatment with a delay >60 mins after embolization, as is often the case in the clinical situation.     

Comparison of hydroxyethyl starch and lactated Ringer's solution on hemodynamics and oxygen transport of critically ill patients in prospective crossover studies

The cardiopulmonary effects of lactated Ringer's solution (RL) were compared with those of 10% hydroxyethyl starch, hetastarch (HES), given in 44 therapeutic interventions in 15 critically ill patients by crossover design. Each agent was given to each patient at least once; seven patients received each agent twice. Infusions were continued until the wedge pressure (WP) had increased to 16 +/- 2 mm Hg in trauma patients and 18 +/- 2.mm Hg in cardiac patients. HES 10% produced significantly increased cardiac index, left and right ventricular stroke work index, CVP, WP, oxygen delivery, oxygen consumption, and reduced pulmonary vascular resistance index (PVRI). RL increased CVP, WP, and PVRI, but did not significantly improve other hemodynamic or oxygen transport variables.     

Effect of arrest time and cerebral perfusion pressure during cardiopulmonary resuscitation on cerebral blood flow, metabolism, adenosine triphosphate recovery, and pH in dogs.

OBJECTIVES: To test the hypothesis that greater cerebral perfusion pressure (CPP) is required to restore cerebral blood flow (CBF), oxygen metabolism, adenosine triphosphate (ATP), and intracellular pH (pHi) levels after variable periods of no-flow than to maintain them when cardiopulmonary resuscitation (CPR) is started immediately. DESIGN: Prospective, randomized, comparison of three arrest times and two perfusion pressures during CPR in 24 anesthetized dogs. SETTING: University cerebral resuscitation laboratory. INTERVENTIONS: We used radiolabeled microspheres to determine CBF and magnetic resonance spectroscopy to derive ATP and pHi levels before and during CPR. Ventricular fibrillation was induced, epinephrine administered, and thoracic vest CPR adjusted to provide a CPP of 25 or 35 mm Hg after arrest times of O, 6, or 12 mins. MEASUREMENTS AND MAIN RESULTS: When CPR was started immediately after arrest with a CPP of 25 mm Hg, CBF and ATP were 57 +/- 10% and 64 +/- 14% of prearrest (at 10 mins of CPR). In contrast, CBF and ATP were minimally restored with a CPP at 25 mm Hg after a 6-min arrest time (23 +/- 5%, 16 +/- 5%, respectively). With a CPP of 35 mm Hg, extending the no-flow arrest time from 6 to 12 mins reduced reflow from 71 +/- 11% to 37 +/- 7% of pre-arrest and reduced ATP recovery from 60 +/- 11% to 2 +/- 1% of pre-arrest. After 6- or 12-min arrest times, brainstem blood flow was restored more than supratentorial blood flow, but cerebral pHi was never restored. CONCLUSIONS: A CPP of 25 mm Hg maintains supratentorial blood flow and ATP at 60% to 70% when CPR starts immediately on arrest, but not after a 6-min delay. A higher CPP of 35 mm Hg is required to restore CBF and ATP when CPR is delayed for 6 mins. After a 12-min delay, even the CPP of 35 mm Hg is unable to restore CBF and ATP. Therefore, increasing the arrest time at these perfusion pressures increases the resistance to reflow sufficient to impair restoration of cerebral ATP.     

Effects of perfusion pressure on tissue perfusion in septic shock

OBJECTIVE: To measure the effects of increasing mean arterial pressure (MAP) on systemic oxygen metabolism and regional tissue perfusion in septic shock. DESIGN: Prospective study. SETTING: Medical and surgical intensive care units of a tertiary care teaching hospital. PATIENTS: Ten patients with the diagnosis of septic shock who required pressor agents to maintain a MAP > or = 60 mm Hg after fluid resuscitation to a pulmonary artery occlusion pressure (PAOP) > or = 12 mm Hg. INTERVENTIONS: Norepinephrine was titrated to MAPs of 65, 75, and 85 mm Hg in 10 patients with septic shock. MEASUREMENTS AND MAIN RESULTS: At each level of MAP, hemodynamic parameters (heart rate, PAOP, cardiac index, left ventricular stroke work index, and systemic vascular resistance index), metabolic parameters (oxygen delivery, oxygen consumption, arterial lactate), and regional perfusion parameters (gastric mucosal Pco2, skin capillary blood flow and red blood cell velocity, urine output) were measured. Increasing the MAP from 65 to 85 mm Hg with norepinephrine resulted in increases in cardiac index from 4.7+/-0.5 L/min/m2 to 5.5+/-0.6 L/min/m2 (p < 0.03). Arterial lactate was 3.1+/-0.9 mEq/L at a MAP of 65 mm Hg and 3.0+/-0.9 mEq/L at 85 mm Hg (NS). The gradient between arterial P(CO2) and gastric intramucosal Pco2 was 13+/-3 mm Hg (1.7+/-0.4 kPa) at a MAP of 65 mm Hg and 16+/-3 at 85 mm Hg (2.1+/-0.4 kPa) (NS). Urine output at 65 mm Hg was 49+/-18 mL/hr and was 43+/-13 mL/hr at 85 mm Hg (NS). As the MAP was raised, there were no significant changes in skin capillary blood flow or red blood cell velocity. CONCLUSIONS: Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism, skin microcirculatory blood flow, urine output, or splanchnic perfusion.     

Reducing ventilation frequency during cardiopulmonary resuscitation in a porcine model of cardiac arrest

INTRODUCTION: American Heart Association/American College of Cardiology guidelines recommend a compression-to-ventilation ratio (C/V ratio) of 15:2 during cardiopulmonary resuscitation (CPR) for out-of-the-hospital cardiac arrest. Recent data have shown that frequent ventilations are unnecessary and may be harmful during CPR, since each positive-pressure ventilation increases intrathoracic pressure and may increase intracranial pressure and decrease venous blood return to the right heart and thereby decrease both the cerebral and coronary perfusion pressures. HYPOTHESIS: We hypothesized that reducing the ventilation rate by increasing the C/V ratio from 15:2 to 15:1 will increase vital-organ perfusion pressures without compromising oxygenation and acid-base balance. METHODS: Direct-current ventricular fibrillation was induced in 8 pigs. After 4 min of untreated ventricular fibrillation without ventilation, all animals received 4 min of standard CPR with a C/V ratio of 15:2. Animals were then randomized to either (A) a C/V ratio of 15:1 and then 15:2, or (B) a C/V ratio of 15:2 and then 15:1, for 3 min each. During CPR, ventilations were delivered with an automatic transport ventilator, with 100% oxygen. Right atrial pressure, intratracheal pressure (a surrogate for intrathoracic pressure), aortic pressure, and intracranial pressure were measured. Coronary perfusion pressure was calculated as diastolic aortic pressure minus right atrial pressure. Cerebral perfusion pressure was calculated as mean aortic pressure minus mean intracranial pressure. Arterial blood gas values were obtained at the end of each intervention. A paired t test was used for statistical analysis, and a p value < 0.05 was considered significant. RESULTS: The mean +/- SEM values over 1 min with either 15:2 or 15:1 C/V ratios were as follows: intratracheal pressure 0.93 +/- 0.3 mm Hg versus 0.3 +/- 0.28 mm Hg, p = 0.006; coronary perfusion pressure 10.1 +/- 4.5 mm Hg versus 19.3 +/- 3.2 mm Hg, p = 0.007; intracranial pressure 25.4 +/- 2.7 mm Hg versus 25.7 +/- 2.7 mm Hg, p = NS; mean arterial pressure 33.1 +/- 3.7 mm Hg versus 40.2 +/- 3.6 mm Hg, p = 0.007; cerebral perfusion pressure 7.7 +/- 6.2 mm Hg versus 14.5 +/- 5.5 mm Hg, p = 0.008. Minute area intratracheal pressure was 55 +/- 17 mm Hg . s versus 22.3 +/- 10 mm Hg . s, p < 0.001. End-tidal CO(2) with 15:2 versus 15:1 was 24 +/- 3.6 mm Hg versus 29 +/- 2.5 mm Hg, respectively, p = 0.001. Arterial blood gas values were not significantly changed with 15:2 versus 15:1 C/V ratios: pH 7.28 +/- 0.03 versus 7.3 +/- 0.03; P(aCO(2)) 37.7 +/- 2.9 mm Hg versus 37.6 +/- 3.5 mm Hg; and P(aO(2)) 274 +/- 36 mm Hg versus 303 +/- 51 mm Hg. CONCLUSIONS: In a porcine model of ventricular fibrillation cardiac arrest, reducing the ventilation frequency during CPR by increasing the C/V ratio from 15:2 to 15:1 resulted in improved vital-organ perfusion pressures, higher end-tidal CO(2) levels, and no change in arterial oxygen content or acid-base balance.     

Hypertonic saline (7.2%) in 6% hydroxyethyl starch reduces intracranial pressure and improves hemodynamics in a placebo-controlled study involving stable patients with subarachnoid hemorrhage

OBJECTIVE: To compare the effects of a bolus infusion of hypertonic saline hydroxyethyl starch with the effects of normal saline (placebo) on intracranial pressure (ICP) and cerebral perfusion pressure in patients with spontaneous subarachnoid hemorrhage. DESIGN AND SETTING: Prospective, randomized, single-blinded, placebo-controlled study in a university hospital. PATIENTS: A total of 22 mechanically ventilated patients with spontaneous subarachnoid hemorrhage with stable ICP between 10 and 20 mm Hg. INTERVENTIONS: During the course of 30 mins, 2 mL/kg of either 7.2% saline in 6% hydroxyethyl starch 200/0.5 (HSS) or of normal saline was infused. The effects were observed for another 180 mins. MEASUREMENTS AND MAIN RESULTS: Mean change in ICP after intervention (DeltaICP) calculated from the average of all observations was -3.3 (sd 2.6) mm Hg in the HSS group vs. -0.3 (sd 1.3) mm Hg in the normal saline group. Mean difference between the groups (HSS - normal saline) was -3.0 mm Hg (95% confidence interval, -4.9 to -1.1; p = .004). Mean peak change after HSS was -5.6 (range, -0.8 to -12.2) mm Hg after 64 (range, 40 to 115) mins. Mean difference in cerebral perfusion pressure change between the groups (HSS - normal saline) was 5.4 mm Hg (95% confidence interval, 2.2 to 8.6; p = .002), and mean difference in cardiac index change, measured as the area under the curve for the whole study period, corresponded to 0.2 L.min.m (95% confidence interval, 0.03 to 0.4; p = .025). CONCLUSIONS: In this placebo-controlled study involving spontaneous subarachnoid hemorrhage patients with normal to moderately increased ICP, 2 mL/kg HSS reduced ICP and increased cerebral perfusion pressure significantly. Maximum effect was reached at twice the infusion time of 30 mins. There were also beneficial hemodynamic effects with increased cardiac index in the HSS group.     

Resuscitation with polyethylene glycol-modified human hemoglobin improves microcirculatory blood flow and tissue oxygenation after hemorrhagic shock in awake hamsters

OBJECTIVE: To determine whether resuscitation with polyethylene glycol-modified human hemoglobin (MalPEG-Hb), an oxygen-carrying blood replacement fluid with 4 g/dL Hb, viscosity of 2.5 cP, colloid osmotic pressure of 49 mm Hg, and p50 of 5.5 mm Hg, improves systemic and microvascular variables after hemorrhage compared with shed blood (SB) and 5% hydroxyethyl starch (HES). SETTING: Laboratory. SUBJECTS: Golden Syrian hamsters. DESIGN: Prospective study. INTERVENTIONS: Hamsters implemented with a skin fold chamber were hemorrhaged 50% of blood volume and resuscitated with 50% shed blood volume (SB, HES, or MalPEG-Hb). MEASUREMENTS AND MAIN RESULTS: Shock and resuscitation were monitored for 1 hr each. Microvascular events were characterized in terms of vessel diameter, flow velocity, functional capillary density, and Po(2) in arterioles, venules, and extravascular tissue. Systemic variables include mean arterial pressure, heart rate, Po(2), Pco(2), pH, and base excess. MalPEG-Hb resuscitation increased functional capillary density to 64% vs. 44% for SB and 32% for HES relative to baseline before shock. Microvascular flow increased 16% for MalPEG-Hb relative to baseline and remained decreased by 44% for SB and 80% for HES. Hemoglobin concentration was 10.4 g/dL with SB, 7.5 (6.8 g/dL in red blood cells and 0.9 g/dL in plasma) with MalPEG-Hb, and 7.5 g/dL with HES, leading to tissue Po(2) of 19, 8, and 5 mm Hg respectively. Calculations of oxygen extraction show that 0.9 g/dL of MalPEG-Hb increased oxygen extraction per gram of red cell hemoglobin in the tissue analyzed compared with SB. These measurements correlate well with a systemic indicator of recovery, base excess, 5.4 +/- 4.7 (MalPEG-Hb), 1.7 +/- 3.8 (SB), and -0.3 +/- 5.7 (HES). CONCLUSION: The presence of 0.9 g/dL of high oxygen affinity MalPEG-Hb improves microvascular blood flow and oxygen transport during shock to a significantly greater extent than that attainable with blood or HES.     

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis

OBJECTIVE: To determine whether nonconvulsive electrographic post-traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. DESIGN: Prospective monitoring with retrospective data analysis. SETTING: Single center academic neurologic intensive care unit. PATIENTS: Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3-13). MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within-subject design, post-traumatic seizures resulted in episodic increases in intracranial pressure (22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 +/- 16 vs. 23.8 +/- 7.6; p < .001) in the seizure group. Using a between-subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). CONCLUSION: Post-traumatic seizures result in episodic as well as long-lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury.     

Effects of early and late intravenous norepinephrine infusion on cerebral perfusion,microcirculation, brain-tissue oxygenation,and edema formation in brain-injured rats

OBJECTIVES: Reduction of cerebral perfusion during the early phase after traumatic brain injury is followed by a later phase of normal to increased perfusion. Thus, pharmacologically elevating mean arterial blood pressure with the aim of improving cerebral perfusion may exert different time-dependent effects on cortical perfusion, microcirculation, tissue oxygenation and brain edema formation after traumatic brain injury. DESIGN: Randomized, placebo-controlled trial. SETTING: Experimental laboratory at a university hospital. SUBJECTS: A total of 37 male Sprague-Dawley rats subjected to a focal cortical contusion. INTERVENTIONS: At 4 or 24 hrs after focal traumatic brain injury, mean arterial blood pressure was increased to 120 mm Hg for 90 mins by infusing norepinephrine. In rats receiving physiologic saline, mean arterial blood pressure remained unchanged. In the first series, pericontusional cortical perfusion was measured using the laser Doppler flowmetry scanning technique before injury and before, during, and after the infusion period. In a second series, intracranial and cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen measured within the contused and pericontusional cortex were recorded continuously before, during, and after norepinephrine infusion. Changes in cortical microcirculation were investigated by orthogonal polarization spectral imaging. At the end of each experiment, hemispheric swelling and water content were determined gravimetrically. MEASUREMENTS AND MAIN RESULTS: At 4 and 24 hrs after traumatic brain injury, intravenous norepinephrine significantly increased pericontusional cortical perfusion, which was also reflected by an increase in diameters and flow velocities of pericontusional arterioles and venules. Cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen were significantly increased during norepinephrine infusion at 4 and 24 hrs. Hemispheric swelling and water content showed no difference between the groups. CONCLUSIONS: After cortical impact injury, early and late intravenous norepinephrine infusion pressure-dependently increased cerebral perfusion and tissue oxygenation without aggravating or reducing brain edema formation. Future studies are warranted to determine long-term changes of short and prolonged norepinephrine-induced increases in mean arterial blood pressure and cerebral perfusion pressure.     

Intracranial pressure and cerebral perfusion pressure in patients developing brain death

PurposeWe investigated whether a critical rise of intracranial pressure (ICP) leading to a loss of cerebral perfusion pressure (CPP) could serve as a surrogate marker of brain death (BD).Materials and methodsWe retrospectively analyzed ICP and CPP of patients in whom BD was diagnosed (n = 32, 16-79 years). Intracranial pressure and CPP were recorded using parenchymal (n = 27) and ventricular probes (n = 5). Data were analyzed from admission until BD was diagnosed.ResultsIntracranial pressure was severely elevated (mean ± SD, 95.5 ± 9.8 mm Hg) in all patients when BD was diagnosed. In 28 patients, CPP was negative at the time of diagnosis (− 8.2 ± 6.5 mm Hg). In 4 patients (12.5%), CPP was reduced but not negative. In these patients, minimal CPP was 4 to 18 mm Hg. In 1 patient, loss of CPP occurred 4 hours before apnea completed the BD syndrome.ConclusionsBrain death was universally preceded by a severe reduction of CPP, supporting loss of cerebral perfusion as a critical step in BD development. Our data show that a negative CPP is neither sufficient nor a prerequisite to diagnose BD. In BD cases with positive CPP, we speculate that arterial blood pressure dropped below a critical closing pressure, thereby causing cessation of cerebral blood flow.     

Heart rate variability after acute traumatic brain injury in children

OBJECTIVE: To evaluate heart rate variability (HRV) by power spectral analysis of heart rate and its relationship to intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcomes in children with acute traumatic head injury. DESIGN: Prospective, case series. SETTING: Pediatric intensive care unit in a level II trauma center/children's hospital. SUBJECTS: Fifteen critically ill children with documented acute traumatic brain injury and four control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The normalized total power from 0.04 to 0.15 Hz was used to quantify low-frequency HRV and from 0.15 to 0.40 Hz to quantify high-frequency HRV. The ratio of low- to high-frequency (LF/HF) power was used as a measure of sympathetic modulation of heart rate. The power spectral data from the 5-min samples were averaged over each hour of data collection, and an hourly LF/HF ratio was obtained based on a 60-min electrocardiogram collection (twelve 5-min segments). The daily mean LF/HF ratio was calculated from the hourly LF/HF measurements. We found no linear correlation between the LF/HF ratio and either ICP or CPP (p = NS). There was a significant decrease in the LF/HF ratio when the intracranial pressure was >30 mm Hg (p < .001) or the cerebral perfusion pressure was <40 mm Hg (p < .001). Children with a Glasgow Coma Scale score of 3-4 had a lower LF/HF ratio compared with those who had a Glasgow Coma Scale score of 5-8 (p < .005). Patients who progressed to brain death had a markedly lower LF/HF ratio (p < .001), with a significant decrease after the first 4 hrs of hospitalization. Patients with more favorable outcomes had significantly higher LF/HF ratios. CONCLUSIONS: Our findings suggest that an ICP of >30 mm Hg or a CPP of <40 mm Hg may be associated with marked autonomic dysfunction and poor outcome. We speculate that HRV power spectral analysis may be a useful adjunct in determining the severity of neurologic insult and the prognosis for recovery in children. The LF/HF ratio may be helpful not only in identifying those patients who will progress to brain death but also in predicting which patients will have favorable outcomes.     

Induced abdominal compartment syndrome increases intracranial pressure in neurotrauma patients: a prospective study.

OBJECTIVE: To evaluate the effect of a stepwise increase in intra-abdominal pressure (IAP) on intracranial pressure (ICP) and to further define the pressure transmission characteristics of different body compartments. DESIGN: A prospective, nonrandomized study. SETTING: A multidisciplinary intensive care unit at a university medical center. PATIENTS: Fifteen patients with moderate-to-severe head injury. INTERVENTIONS: All patients were studied after the initial stabilization and resolution of intracranial hypertension. Measurements were carried out before and 20 mins after IAP was increased by positioning a soft, 15-L water bag on the patient's abdomen. MEASUREMENTS AND MAIN RESULTS: Placing weights upon the abdomen generated a significant increase in IAP, which rose from 4.7 +/- 2.9 to 15.5 +/- 4.1 mm Hg (p <.001). The rise in IAP caused concomitant and rapid increases in central venous pressure (from 6.2 +/- 2.4 to 10.4 +/- 2.9 mm Hg; p <.001), internal jugular pressure (from 11.9 +/- 3.2 to 14.3 +/- 2.4 mm Hg; p <.001), and ICP (from 12.0 +/- 4.2 to 15.5 +/- 4.4 mm Hg; p <.001). Thoracic transmural pressure, calculated as the difference between central venous pressure and esophageal pressure, remained constant during the protocol. Respiratory system compliance decreased from 58.9 +/- 9.8 to 44.9 +/- 9.4 mL/cm H2O (p <.001) in all patients because of decreased chest wall compliance. The mean arterial pressure increased from 94 +/- 11 to 100 +/- 13 mm Hg (p <.01), which allowed the maintenance of a stable cerebral perfusion pressure (82.4 +/- 10.3 vs. 84.7 +/- 11.5 mm Hg; p = NS) despite the ICP increase. CONCLUSIONS: Increased IAP causes a significant rise in ICP in head trauma patients. This effect seems to be the result of an increase in intrathoracic pressure, which causes a functional obstruction to cerebral venous outflow. Routine assessment of IAP may help clinicians to identify remediable causes of increased ICP. Caution should be used when applying laparoscopic techniques in neurotrauma patients.     

Effect of increasing norepinephrine dosage on regional blood flow in a porcine model of endotoxin shock

OBJECTIVE: To evaluate the effect of a norepinephrine-induced differential increase in mean arterial pressure on splanchnic and renal perfusion in a porcine model of volume-resuscitated endotoxic shock. DESIGN: Prospective, controlled, acute interventional study. SETTING: Animal research laboratory. SUBJECTS: Fourteen landrace pigs, seven treated with norepinephrine and seven used as endotoxemic controls. INTERVENTIONS: In an acute endotoxic shock model, norepinephrine was used to reverse hypotension in seven fluid-resuscitated pigs, anesthetized with alpha-chloralose and equipped with flow probes around the portal vein and renal artery, renal and jejunal mucosal laser Doppler flowmetry, and jejunal tonometry. Mean arterial pressure was increased by 10 and then 20 mm Hg above the shock level with norepinephrine. Seven shocked, fluid-resuscitated only animals served as the comparison group. MEASUREMENTS AND MAIN RESULTS: Measurements were performed before 2-hr endotoxin infusion and at the end of each increased level of mean arterial pressure. Raising mean arterial pressure with norepinephrine by 10 mm Hg significantly increased cardiac output, systemic oxygen extraction, and portal vein blood flow; stabilized metabolic acidosis; and tended to restore renal and jejunal mucosal flows to preshock levels. Increasing mean arterial pressure by 20 mm Hg further increased cardiac output and oxygen delivery but without improving portal vein, renal artery, and jejunal mucosal blood flows. CONCLUSIONS: Norepinephrine, administered to increase mean arterial pressure by 10 mm Hg in an acute model of volume-resuscitated endotoxic shock, improved systemic and regional perfusion. The administration of norepinephrine to increase mean arterial pressure 20 mm Hg above shock did not increase renal and splanchnic blood flows, despite an enhanced cardiac output.     

Augmentation of postischemic brain damage by severe intermittent hypertension

The neurological recovery and histological changes were studied in monkeys after intermittent postischemic arterial hypertension after 16 min of global brain ischemia. Ischemia was produced with a high pressure (1500 mm Hg) neck tourniquet and systemic arterial hypotension. Intensive care and life support, including monitoring of physiological variables, were provided for 7 days. Postischemia all monkeys were immobilized; ventilation was controlled and mean arterial pressure was maintained between 85--115 mm Hg for the first 48 hours. Immediately postischemia in four monkeys, intermittent arterial hypertension (i.e., 150--190 mm Hg) was induced by norepinephrine infusion for 3--5 min. Hypertensive episodes were repeated at 15, 30, 60, and 120 min postischemia, once every hour for the first 24 hours and once every 2 hours between 24 and 48 hours. Thereafter, the monkeys were allowed to breathe spontaneously. Four control monkeys were similarly treated except that arterial hypertension was not induced. Neurological recovery was evaluated by EEG, intracranial pressure, neurological deficit scoring, and histological examination of the brain after killing on day 7 postischemia. The neurological deficit score (100 % = brain death; 50% = vegetative state; 0% = normal) in control monkeys on day 7 was 17.8 +/- 1.8 (SEM) % compared to 46.3 +/- 6.5% (p less than 0.05) in the hypertension group. EEG recovery was delayed and the postischemic increase in intracranial pressure was prolonged in the hypertension group. Histological damage scores in the brain correlated with neurological deficit scores. Severe intermittent hypertension has a deleterious effect on neurological recovery after global brain ischemia.