SHOCK, Vol. 44, Supplement 1, pp. 96Y102, 2015
INTRATHORACIC PRESSURE REGULATION IMPROVES CEREBRAL PERFUSION AND CEREBRAL BLOOD FLOW IN A PORCINE MODEL OF BRAIN INJURY Anja Metzger,*† Jennifer Rees,‡ Young Kwon,‡ Timothy Matsuura,‡ Scott McKnite,§ and Keith G. Lurie*† *Department of Emergency Medicine, University of Minnesota, Minneapolis; † Advanced Circulatory Systems, Inc., Roseville, Minnesota; ‡ Department of Cardiology, University of Minnesota, Minneapolis; and §Minneapolis Medical Research Foundation, Minneapolis, Minnesota Received 1 Oct 2014; first review completed 23 Oct 2014; accepted in final form 5 Dec 2014 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 j12 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 T 2.8 mmHg, 44.0 T 2.7 mmHg, 44.5 T 2.8 mmHg, and 43.1 T 1.9 mmHg, respectively; a significant increase from ICH study baseline (39.5 T 1.7 mmHg) compared with control animals in which mean CPP was 36.7 T 1.4 mmHg (ICH study baseline) and then 35.9 T 2.1 mmHg, 33.7 T 2.8 mmHg, 33.9 T 3.0 mmHg, and 36.0 T 2.7 mmHg at 90, 120, 180, and 240 min, respectively (P G 0.05 for all time points). Cerebral blood flow, as measured by an invasive CBF probe, increased in the IPR group (34 T 4 mL/100 g-min to 49 T 7 mL/ 100 g-min at 90 min) but not in controls (27 T 1 mL/100 g-min to 25 T 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. KEYWORDS—Traumatic brain injury, intracranial pressure, intrathoracic pressure, intrathoracic pressure regulation, cerebral perfusion pressure, intracranial hypertension
INTRODUCTION
Intrathoracic pressure regulation (IPR) is a novel therapy that may be of benefit for the treatment of BI. It can be delivered with a device that is inserted into a standard respiratory circuit between the patient and a means to provide positive pressure ventilation. After each positive pressure ventilation, IPR lowers intrathoracic pressure to subatmospheric levels relative to the rest of the body and thereby enhances blood return to the heart, decreases ICP, and improves cerebral perfusion pressure (CPP). Intrathoracic pressure regulation has previously been studied in animal models of cardiac arrest and hemorrhagic shock (8Y12). Intrathoracic pressure regulation builds on the physiological principles of the inspiratory impedance threshold device, which augments negative intrathoracic pressure during cardiopulmonary resuscitation and in spontaneously breathing applications (13Y26). Intrathoracic pressure regulation relies on similar physiological principles of the impedance threshold device. Although IPR was initially developed as a noninvasive means to increase preload in hypovolemic nonspontaneously breathing patients, it has also been reported to reduce ICP (9, 12). The goal of this study was to test the hypothesis that IPR therapy will increase CPP in a porcine model of intracranial hypertension (ICH).
The current treatment of elevated intracranial pressure (ICP) includes aggressive fluid resuscitation to maintain the mean arterial blood pressure greater than 90 mmHg, control of oxygen and carbon dioxide partial pressures through mechanical ventilation, mild-moderate hyperventilation, sedation, lowering the body temperature, prevention of jugular venous outflow obstruction by head elevation, pharmacological therapy including hyperosmolar agents (e.g., mannitol and hypertonic saline) and anesthetics, cerebrospinal fluid drainage, and decompressive craniotomy (1Y7). Treatments are applied in a stepwise fashion until satisfactory ICP control is achieved. Despite these therapies, elevated ICP and decreased cerebral perfusion remain leading causes of morbidity and mortality for patients with brain injury (BI). Address reprint requests to Anja Metzger, PhD, 1905 County Rd C West Roseville, MN 55113. E-mail:
[email protected]. This study was supported by the Department of Defense Medical Research and Development Program Award: Regulation of Cerebral and Systemic Perfusion Following Traumatic Brain Injury (grant no. W81XWH-11-2-0094). Dr. Anja Metzger is an adjunct assistant professor in the University of Minnesota’s Department of Emergency Medicine. She is also employed by Advanced Circulatory Systems, Inc., the manufacturer of the device used in this study to provide the negative intrathoracic pressure therapy. Dr. Lurie is Chief Medical Officer at Advanced Circulatory Systems, Inc. DOI: 10.1097/SHK.0000000000000314 Copyright Ó 2015 by the Shock Society
METHODS All animal studies were approved by the Institutional Animal Care Committee of the Minneapolis Medical Research Foundation at Hennepin County 96
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FIG. 1. X-ray of contrast-filled 8F Foley catheter balloon to illustrate the pig brain volume occupied in this BI model of ICH. Brain and balloon volume are outlined.
Medical Center. All animals received treatment and care in compliance with the 1996 Guide for the Care and Use of Laboratory Animals by the National Research Council and the American Association for Accreditation of Laboratory Animal Care. Twenty-eight Yorkshire female crossbreed domestic pigs (35.8 T 1.1 kg) received 10 mL (100 mg/mL) of intramuscular ketamine HCl (Ketaset; Fort Dodge Animal Health, Fort Dodge, Iowa) for initial sedation. The trachea was intubated with a 7F cuffed endotracheal tube inflated to prevent air leaks. During the preparatory phase, animals were ventilated under positive pressure and with room air using a volume-controlled ventilator (NarkoMed 2A North American Drager). The ventilator was set to a tidal volume of 10 mL/kg and an FiO2 of 0.5, and respiratory rate was adjusted (average, 12 T 2) to keep oxygen saturation above 96% and end-tidal carbon dioxide (ETCO2) between 38 and 42 mmHg. A femoral arterial sheath was placed with a percutaneous incision and was used to acquire arterial blood gases and continuously measure central aortic pressure via a 5F micromanometer Millar catheter (Mikro-Tip Transducer; Millar Instruments, Inc., Houston, Tex). An intracranial bolt was inserted into the animal’s skull, and ICPs were measured with a 5F micromanometer pressure transducer (Mikro-Tip Transducer; Millar Instruments, Inc.) positioned 0.5 cm into the right parietal lobe of the brain. A second intracranial bolt was inserted just below the first, and a Bowman Perfusion Monitor probe to measure cerebral blood flow (CBF) (Hemedex, Cambridge, Mass) was advanced 3 cm into the white matter of the right parietal lobe. An 8F Foley catheter was placed through a third intracranial bold in the animal’s left hemisphere. The catheter balloon was carefully advanced just underneath the skull but above the dura. The balloon was inflated with 3 mL of saline at a rate of 3 mL/h until a target ICP of at least 25 mmHg was reached. Figure 1 illustrates the brain volume occupied by the inflated balloon. Once inflation was complete, the animals were allowed to stabilize for an additional 30 min. During this time, a 90Y2g/kg per min infusion of succinylcholine was initiated and maintained throughout the study. This neuromuscular blocker is required to inhibit the baroreceptor reflex, which causes the animal to
IPR
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Bbuck[ the ventilator during the expiratory phase when the device is applied. Animals were then prospectively randomized to either treatment with an IPR device (an advanced version of the CirQlator; Advanced Circulatory Systems, Inc., Roseville, Minn) that generates j12 cmH2O airway pressures during the expiratory phase of ventilation or no IPR device. Subsequently, animals were sacrificed, their lungs were harvested, and their brains were examined for evidence of injury. All animals were euthanized with a 10-mol/L potassium solution at the end of the experiment. During the balloon inflation and intervention, ETCO2 was carefully monitored and respiratory rate (between 12 and 20 breaths/min) was adjusted to maintain an ETCO2 level of 40 mmHg to ensure that the effects of the device were not mediated by changes in pCO2 levels. All data including continuous electrocardiogram monitoring were recorded and stored using a computerized data analysis program (BioPac; Biopac Systems, Inc., Goleta, Calif). The ETCO2, tidal volume, and arterial oxygen saturation were recorded with a CO2SMO Plus system (Novametrix Medical Systems, Wallingford, Conn). A pulmonary artery catheter (Swan-Ganz CCOmbo 7.5F; Edwards Lifescience, USA) was inserted and positioned using the pulmonary arterial blood pressure curve and the pulmonary artery wedge pressure curve to monitor continuous cardiac output (Vigilance, Edwards Lifescience, USA). To assess potential pulmonary complications as a result of the IPR therapy, lung samples were harvested after euthanasia of the pigs and inflation fixed in formalin before being sampled and routinely processed to produce glass slideYmounted sections stained with hematoxylin and eosin, which were read by a pathologist blinded to treatment. Serum samples were also collected for interferon-+ (IFN-+) and interleukin-6 (IL-6) enzyme-linked immunosorbent assay analysis at 240 min of study, important biochemical markers of lung injury.
Statistical Analysis Values are expressed as mean T SEM. Hemodynamic, respiratory, and blood gas variables were compared between treatments using a Student t test. A value of P G 0.05 was considered statistically significant.
RESULTS After randomization, the number of animals per group and their respective weights were as follows: 12 pigs (35.4 T 0.7 kg) in the IPR group and 11 pigs (34.6 T 0.7 kg) in the control group. Twenty-three of 28 animals studied qualified for inclusion in the study as pretreatment hemodynamics required that the CPP was less than 50 mmHg to represent a subject with significantly compromised cerebral perfusion. Baseline as well as postYintracranial balloon/pretreatment hemodynamics (referred to as IPR 0 throughout), heart rate, and arterial blood gas parameters were similar between groups. To test the primary hypothesis, we measured mean arterial pressure (MAP), ICP, and calculated CPP for 4 h of treatment. The comparisons of mean values for these parameters are shown in Figure 2. Intrathoracic pressure regulation therapy significantly increased CPP throughout the study from 39.5 T 1.7 mmHg to 43.1 T 1.9 mmHg at 4 h of IPR therapy but remained unchanged in controls (36.7 T 1.4 mmHg to 36.0 T 2.7 mmHg) (P G 0.04). This seems to be driven by a combination of an increase or relative maintenance of MAP and a greater decrease in ICP
FIG. 2. The effect of IPR therapy on CPP, MAP, and ICP throughout the course of the study. *P G 0.05. Baseline represents values before balloon inflation.
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in the treated animals compared with controls. For example, MAP changed from 67.4 T 2.4 mmHg at pretreatment to 65.8 T 2.1 mmHg at 3 h of IPR therapy and from 63.5 T 1.6 mmHg to 58.2 T 3.0 mmHg in control animals, whereas ICP decreased from 26.8 T 0.8 mmHg to 21.1 T 1.1 mmHg in the IPR group at 3 h versus a decrease from 26.7 T 0.8 mmHg to 24.1 T 1.9 mmHg in the control group. Cerebral perfusion pressure in the treatment group returned to prestudy baseline values during the study, whereas, in the control group, CPP never improved during the study. Additional key hemodynamic, arterial blood gas, and respiratory parameters are shown in Table 1. Notably, systolic blood pressures were significantly higher in
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the IPR group throughout the intervention, with the exception of min 240. Heart rate increased during initial IPR use and during the same control period but remained relatively constant throughout the study. The ETCO2 remained constant as per study design by adjusting the ventilator rate. Respiratory rate required to maintain a constant ETCO2 however was significantly less for the IPR therapy group because active withdrawal of CO2 occurs during IPR therapy. Oxygen saturation remained above 98% throughout the study. Blood gas parameters including pH, PaCO2, HCO3, and base excess did not change significantly throughout the study. However, PaO2 was significantly decreased during IPR but was never less than
TABLE 1. Additional hemodynamic, arterial blood gas, and respiratory parameters at baseline and throughout the study Hemodynamic parameters RA, mmHg
Cardiac output, L/min
EtCO2, mmHg Heart rate, beats/min
Treatment group
Baseline
IPR 0 min
IPR 60 min
IPR 90 min
IPR 120 min
IPR 180 min
IPR 240 min
Control
2.6 T 0.4
2.1 T 0.3
1.9 T 0.3
1.7 T 0.4
1.3 T 0.6
1.5 T 1.3
1.8 T 0.4
IPR
4.5 T 0.6
4.8 T 1.4
1.1 T 1.3
j0.5 T 1.4
0.4 T 2.2
j0.9 T 1.7
j0.7 T 2.1
Control
4.4 T 0.2
4.3 T 0.2
3.9 T 0.2
3.5 T 0.2
3.5 T 0.2
3.5 T 0.3
3.6 T 0.2
IPR
3.9 T 0.2
4.3 T 0.2
5.0 T 0.3*
4.6 T 0.2*
4.5 T 0.2*
4.3 T 0.2*
4.2 T 0.2*
Control
40 T 0
40 T 0
40 T 0
40 T 0
40 T 0
40 T 0.4
40 T 0
IPR
40 T 0
40 T 0
40 T 0
40 T 0
40 T 0.1
40 T 0
40 T 0
Control
116 T 7
132 T 8
141 T 9
140 T 8
144 T 8
133 T 6
133 T 6
IPR
94 T 5
125 T 7
133 T 10
131 T 10
132 T 10
134 T 11
131 T 10
Systolic Blood Pressure (mmHg)
Control
87.4 T 2.8
83.3 T 3.2
78.6 T 2.5
78.4 T 2.6
74.7 T 3.2
75.2 T 2.8
73.9 T 3.5
IPR
81.5 T 2.6
89.4 T 2.1
90.2 T 2.4*
88.5 T 2.4*
86.4 T 2.0*
85.0 T 2.1*
82.7 T 2.6
Diastolic Blood Pressure (mmHg)
Control
50.2 T 2.2
50.6 T 2.5
48.2 T 1.6
48.0 T 1.6
44.6 T 2.0
43.7 T 2.5
43.3 T 2.6
IPR
44.1 T 1.6*
51.6 T 2.2
52.2 T 2.0
50.8 T 2.3
49.0 T 1.8
47.9 T 1.7
47.6 T 2.0
IPR 90 min
IPR 120 min
IPR 180 min
IPR 240 min
NA
NA
Blood gas parameters
Baseline 7.47 T 0.01
IPR 0 min 7.49 T 0.01
IPR 60 min 7.48 T 0.01
7.46 T 0.01
Arterial pH
Control IPR
7.43 T 0.01
7.45 T 0.01
7.42 T .01*
NA
NA
7.46 T 0
NA
PaCO2, mmHg
Control
42.9 T 0.5
41.8 T 0.7
41.5 T 0.9
NA
NA
42.2 T 1.0
NA
IPR
44.5 T 1.0
43.6 T 0.9
46.3 T 1.5
NA
NA
45.2 T 1.5
NA
PaO2, mmHg
Control
220.2 T 6.2
205.2 T 7.8
204.5 T 7.0
NA
NA
200.2 T 6.8
NA
IPR
228.3 T 14.1
195.8 T 8.9
131.8 T 8.5*
NA
NA
124.5 T 5.4*
NA
HCO3, mmol/L
Control
31.0 T 0.7
31.5 T 0.5
30.6 T 0.4
NA
NA
30.0 T 0.6
NA
IPR
29.3 T 0.7
30.3 T 0.5
29.9 T 0.6
NA
NA
30.8 T 0.7
NA
Base excess, mmol/L
Control
7.3 T 0.8
8.1 T 0.6
7.0 T 0.5
NA
NA
6.2 T 0.8
NA
%O2 saturation
Control
IPR
IPR Respiratory parameters
NA
4.9 T 0.8
6.3 T 0.6
5.4 T 0.6
NA
NA
6.7 T 0.7
NA
100 T 0
100 T 0
100 T 0
NA
NA
100 T 0
NA
99.9 T 0.1 Baseline
99.8 T 0.1 IPR 0 min
98.3 T 0.4* IPR 60 min
98.6 T 0.2*
NA
NA
IPR 90 min
IPR 120 min
IPR 180 min
IPR 240 min
NA
Control
15.2 T 0.8
18.3 T 1.2
19.2 T 1.4
19.7 T 1.3
20.3 T 1.6
20.0 T 1.3
18.2 T 1.2
IPR
14.3 T 0.6
19.2 T 1.0
14.8 T 0.8
15.5 T 0.7*
15.6 T 0.6*
16.3 T 1.0*
16.0 T 1.4
Expiratory airway pressure, cmH2O
Control
3.4 T 0.1
3.3 T 0.1
IPR
3.7 T 0.1
3.7 T 0.1
j11.3 T 0.1*
j11.3 T 0.2*
j11.3 T 0.2*
j11.3 T 0.2*
j11.3 T 0.3*
Peak inspiratory pressure, cmH2O
Control
16.8 T 0.9
16.4 T 0.7
16.5 T 0.8
16.8 T 0.6
17.1 T 0.7
16.8 T 0.8
17.4 T 0.9
IPR
18.0 T 1.0
19.0 T 1.1
12.6 T 1.0*
12.7 T 1.0*
12.9 T 1.0*
13.7 T 0.9*
13.6 T 0.9*
Tidal volume, mL
Control
335 T 10
302 T 11
300 T 11
298 T 11
302 T 10
302 T 10
319 T 9
IPR
339 T 6
304 T 9
330 T 10
323 T 8
326 T 10
328 T 11
330 T 13
Respiratory rate
3.3 T 0.1
3.4 T 0.1
3.4 T 0.1
3.4 T 0.1
*P G 0.05.
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FIG. 3. The effect of IPR therapy on CBF compared with controls during the first 90 min of the study. Baseline represents cerebral blood flow before balloon inflation. *P G 0.02.
124 mmHg because there seems to be some shunting during IPR use. Notably, cardiac output was significantly higher in the IPR therapy group, which further demonstrates the effect of the IPR therapy on venous return. An important secondary end point was the evaluation of the effect of the device on CBF during the initial evaluation period of 90 min, as shown in Figure 3. Cerebral blood flow, as measured by an invasive CBF probe, increased by 44% in the IPR group (34 T 4 mL/100 g-min to 49 T 7 mL/100 g-min at 90 min) but not in controls (27 T 1 mL/100 g-min to 25 T 5 mL/100 g-min at 90 min) (P = 0.01). Data beyond
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FIG. 4. Average pulmonary injury grade for control and IPR-treated animals as determined by a blinded pathologist. There were no significant differences between groups.
90 min was confounded by the automatic system recalibration that occurs with this device. To gain insight into the effect of IPR therapy on the pulmonary system, 20 lung pathology sections (10 from each lung) from each animal were read by a pathologist blinded to treatment and semiquantitatively graded for ruptured alveoli, atelectasis, thickened septal wall, and inflammation according to the grading scale in Table 2. The results are summarized in Figure 4. In general, lung histology between groups was unremarkable. The presence of atelectasis within any section was
TABLE 2. Semiquantitative grading scale used for sectioned lung samples to evaluate pulmonary injury in control and IPR groups Category Ruptured alveoli
Atelectasis
Thickened septal wall
Inflammation
Grade
Definition of grade
0
G5 ruptured alveoli per 5 random 20 fields
1
5 Y 10 ruptured alveoli per 5 random 20 fields
2
11 Y 15 ruptured alveoli per 5 random 20 fields
3
16 Y 20 ruptured alveoli per 5 random 20 fields
4
21+ ruptured alveoli per 5 random 20 fields
0
No atelectasis noted
1
G25% atelectasis in whole section
2
25% Y 50% atelectasis in whole section
3
50% Y 75% atelectasis in whole section
4
975% atelectasis in whole section
0
No septal walls are thickened
1
Septal walls are between 1 and 2 cells thick in 0% Y 25% of the section
2
Septal walls are between 1 and 2 cells thick in 25% Y 50% of the section
3
Septal walls are between 1 and 2 cells thick in 950% of the section
4
Septal walls are greater than 2 cells thick in any amount of the section
0
No inflammation present
1
Neutrophils present multifocally in septal walls
2
Neutrophils present multifocally in septal walls and alveolar spaces
3
Neutrophils present multifocally in septal walls, alveolar spaces and airways
4
Neutrophils are present diffusely within the section
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FIG. 5. Effect of the IPR on carotid blood flow, airway pressure, aortic pressure, ICP, and right atrial pressure in an intact and open thorax of a pig subjected to 45% hemorrhage. The IPR effect on ICP is solely dependent on the generation of negative intrathoracic pressure. In the open-thorax model, negative intrathoracic pressure is not generated. As such, there is no effect on ICP or right atrial pressure. Note, peak inspiratory pressures in the intact-thorax model are significantly reduced when IPR therapy is initiated.
very minimal and usually confined to a small areaVthere was no discernible pattern to the presence of the atelectasis from lung sections within any one individual animal or between animals. There were low numbers of animals with greater than five sections containing atelectasis that only occurred on one side of the lungs (i.e., right or left side), indicating causation from prolonged recumbency on one side during anesthesia. Furthermore, serum levels of cytokines IL-6 and IFN-+ levels showed no significant differences between groups. Interleukin-6 levels were 0.21 T 0.01 pg/mL for controls and 0.21 T 0.01 pg/mL for the IPR group. Interferon-+ levels were unreactive in both groups for the majority of the samples. Autopsy findings were unremarkable; in particular, there was no evidence of lung injury but brain depression was evident as a result of the BI. Importantly, peak inspiratory pressures are significantly less when IPR therapy is used as the expiratory airway pressures are j12 cmH2O; ventilating into lungs with pressures starting at j12 cmH2O results in a significantly less peak inspiratory pressure (PIP) than ventilating into lungs with pressures starting at 3 cmH2O. The reduction in PIP is shown in Figure 5 when IPR therapy is applied. We speculate that this may be why no evidence of pulmonary injury was observed during IPR therapy. DISCUSSION Intrathoracic pressure regulation provides a noninvasive means to potentially improve cerebral perfusion and brain blood flow resulting from BI. Results from this study demonstrated for the first time that CPP was significantly increased by the IPR device in this model of ICH. Intrathoracic pressure regulation initially lowered ICP in this balloon mass effect model but, as circulation to the brain increased, so did ICP. As such, both the increase in MAP and the decrease in ICP contributed to the observed increase in CPP compared with those in controls. These findings suggest that IPR therapy may be of clinical value in patients with increased ICP and decreased cerebral perfusion. The mechanism of pressure transfer from the thorax to the brain during IPR therapy remains speculative but is most likely through the paravertebral venous sinuses. This physiology was previously studied by Guerci et al. (27)
when assessing the transfer of positive pressure from the thorax to the cranium. They observed that a positive pressure within the thorax was immediately transmitted to the brain via the paravertebral sinuses in the thorax in a cardiopulmonary resuscitation model. In prior unpublished IPR studies on the mechanism of pressure transfer from the thorax to the brain in the same porcine model, we observed the same magnitude of reduction in ICP and increase in CPP with IPR therapy with and without temporary ligation of the internal and external jugular veins. We speculate based on the work of Guerci et al. (27) and our earlier studies that, similar to the mechanism of positive pressure transmission from the thoracic cavity to the cranial space, a reduction in intrathoracic pressure is also immediately transmitted via the paravertebral sinuses. In addition, when the thorax was opened (via a subcostal incision through the diaphragm and pleural spaces bilaterally, exposing the thorax cavity to atmospheric pressure), application of IPR therapy caused the lung to deflate below functional residual capacity and an increase in cardiac filling and cardiac output was observed, but ICP increased instead of decreased (Fig. 5). Without a means to transmit airway pressures through thoracic structures to the paravertebral veins when the thorax was open, ICP did not decrease but rather increased as cardiac output increased. Optimizing this newly discovered mechanism may have significant implications for the treatment of hypotension and increased ICP. What is clear from this mechanistic research is that a reduction in intrathoracic pressure translates directly into a reduction in ICP. This finding highlights the importance of cardiac-pulmonary-cranial interactions in the treatment of BI. The effect of the IPR therapy was observed in this relatively mild elevation of ICP model. A pilot evaluation of this technology in patients has also demonstrated a reduction in ICP and an increase in CPP (28). Additional studies comparing this treatment to current ICP management strategies such as hyperventilation and mannitol are currently underway. In a pilot animal study, an 82-mL bolus of 20% mannitol resulted in a reduction in ICP from 34 to 29 mmHg 15 min after bolus, but there was no effect on CPP. In contrast, in this same animal, IPR therapy resulted in a
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IPR FOR ICH
reduction in ICP from 31 to 24 mmHg and a resultant increase in CPP (from 47 to 60 mmHg). LIMITATIONS There are several limitations to this evaluation of IPR therapy for the treatment of BI. The epidural balloon inflation model is one of several animal models used to examine the effect of an intervention on elevated ICP or compromised CPP commonly seen in traumatic BIs (29Y31). We recognize that this model simplifies the complex interactions of secondary brain injury and, importantly, that there was no known active ongoing bleeding or known disruption in the blood-brain barrier. It is unknown whether IPR therapy will help or hurt the brain in the setting of ongoing intracranial bleeding. Second, the presence of the balloon and the three intracranial bolts in the relatively small brain volume of this animal model may somewhat mask the true effect of the therapy. Furthermore, 4 h of use represents a relatively short duration in the general treatment of brain injured patients; a 24-h porcine study is in progress. An interim histological analysis shows no significant differences between groups in the pulmonary histology after 24 h of use. Also, the effects of IPR therapy on lung function in patients with compromised lungs remain unknown. In this study, pO2 levels were significantly reduced during IPR therapy but, with supplemental O2 at an FiO2 of 0.5, the oxygen saturation remained greater than 98%. Furthermore, in studies with IPR in hypovolemic pigs for up to 4 h of application, there was no change in lung compliance, no evidence of an increase in lung water pulmonary edema by chest x-ray, and no change in molecular markers of lung injury including IL-1", IL-6, IL-8, and tumor necrosis factor-! (unpublished data from our laboratory). At least in pigs with normal lung function, IPR therapy did not adversely affect lung function after 4 h of continuous use. CONCLUSIONS In this anesthetized pig model of ICH, treatment with IPR therapy significantly improved CPP and CBF and decreased ICP. No adverse device effects were observed. This noninvasive therapy may be of clinical value in optimizing cerebral perfusion in states of elevated ICP and compromised cerebral perfusion. REFERENCES 1. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS-CNS; Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al.: Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma 24(Suppl 1): S14YS20, 2007. 2. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS-CNS; Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al.: Guidelines for the management of severe traumatic brain injury. III. Prophylactic hypothermia. J Neurotrauma 24(Suppl 1): S21YS25, 2007. 3. Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS-CNS; Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, et al.: Guidelines for the management of severe traumatic brain injury. V. Deep vein thrombosis prophylaxis. J Neurotrauma 24(Suppl 1):S32YS36, 2007.
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