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Ann Thorac Surg 2000;69:578-583
© 2000 The Society of Thoracic Surgeons

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Original Articles

Utility of near-infrared spectroscopic measurements during deep hypothermic circulatory arrest

^a Department of Cardiovascular Surgery, Children’s Hospital, Boston, Massachusetts, USA
^b Department of Neurology, Children’s Hospital, Boston, Massachusetts, USA
^c Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA
^d Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA

Address reprint requests to Dr Jonas, Department of Cardiovascular Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115
e-mail: jonas_r{at}al.tch.harvard.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Near-infrared spectroscopy (NIRS) is used to monitor cerebral oxygenation during cardiac surgery. However, interpretation of the signals is controversial. The aim of the study was to determine which NIRS variable best correlated with brain damage as assessed by animal behavior and neurohistologic score and to compare the accuracy of NIRS and magnetic resonance spectroscopy (MRS) in predicting brain injury.

Methods. Forty 5-week-old piglets underwent 60 minutes of deep hypothermic circulatory arrest (DHCA) at 15°C. Changes in brain adenosine triphosphate (ATP), phosphocreatine (PCr), and intracellular pH (pHi) were determined by MRS and correlated to changes in oxygenated hemoglobin (HbO₂), deoxygenated hemoglobin (Hb), and oxidized cytochrome a,a₃ (CytOx) NIRS signals. Brains were fixed on day 4 and examined using a neurohistologic score.

Results. Reductions in CytOx and HbO₂ values were correlated closely with decreases in ATP, PCr, and pHi. The changes in CytOx and PCr showed the strongest correlation (r = 0.623). Maximal CytOx reduction during DHCA of more than -25 µM * differential pathlength factor (DPF) predicted brain damage with a sensitivity of 100% and a specificity of 75%. The histologic score was also correlated with a decrease in ATP (r = -0.52 for CytOx; r = -0.32 for ATP); HbO₂, PCr, and pHi showed no correlations.

Conclusions. Reduction in CytOx correlates with decreased brain energy state and predicts histologic brain injury after DHCA with a high sensitivity. These data suggest that the level of CytOx could be a very important predictor of brain damage during DHCA.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Near-infrared spectroscopy (NIRS) is a noninvasive optical monitoring technique that can provide information on changes in cerebral oxyhemoglobin (HbO₂), deoxyhemoglobin (Hb), and oxidized cytochrome a,a₃ (CytOx) concentrations in brain tissues [1]. The usefulness of these measurements has been questioned because the measurements are relative, and CytOx provides a small signal [2]. In addition, studies that directly compare these measurements with changes in cerebral energetics are limited [3, 4]. We have developed a survival piglet model of deep hypothermic circulatory arrest (DHCA) in which we measured cerebral adenosine triphosphate (ATP), phosphocreatine (PCr), and intracellular pH (pHi) with P31 nuclear magnetic resonance spectroscopy (MRS) in parallel with NIRS measurements [5, 6]. Neurologic evaluation was continued for 4 days, at which time the brain was fixed for histology. We previously used this experimental model to evaluate the relations of neurologic outcome with variations of perfusate hematocrit or perfusate colloid oncotic pressure under conditions similar to those used in neonatal cardiac surgery [5, 6].

We now report the correlation between NIRS and MRS measurements by combining results from these two earlier studies with the exact same operative protocol to overcome the statistical limitations of small experimental numbers. Intraoperative changes in MRS and NIRS measurements, which may be indicators of the extent of ischemic metabolic changes, were compared with neurologic and histologic outcome.

	Material and methods

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Experimental preparation
All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated for the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Science (NIH Publication No. 86-23, revised in 1985).

Details of the experimental preparations have been described previously [5, 6]. Briefly, 40 5-week-old Yorkshire piglets were anesthetized with intraperitoneal sodium methohexital (45 mg/kg) and intubated. Anesthesia was maintained by continuous infusion of fentanyl (25 µg · kg^-1 · h^-1), midazolam (0.2 mg · kg^-1 · h^-1), and pancuronium (0.2 mg · kg^-1 · h^-1) throughout the entire experiment except during the period of circulatory arrest. Before surgery, a 3.0-cm diameter surface coil was sutured on the scalp overlying the cerebral hemispheres, and a pair of fiberoptic optodes for NIRS measurements was attached to the head of the animal. The optode spacing was 3.0 to 3.5 cm in the coronal plane.

After systemic heparinization (300 IU/kg), an 8F arterial cannula and a 24F venous cannula were inserted into the right femoral artery and right atrium, respectively. The animal was then placed in a 40-cm diameter horizontal-bore superconducting 4.7 T magnet (Oxford Research System, Oxford, England) and subjected to hypothermic cardiopulmonary bypass (CPB; 40 minutes of cooling, pH-stat strategy, hematocrit between 0.10 and 0.30) and 60 minutes of circulatory arrest at 15°C nasopharyngeal. Upon termination of the experiment after 45 minutes of rewarming, the piglet was weaned off CPB and decannulated outside the magnet. Protamine (6 mg/kg) was administered intravenously. Immediately after decannulation, the animal was repositioned in the bore for 3 hours for MRS and NIRS data collection. After that period, all incisions were closed in a sterile fashion and the animal was left intubated during the first 12 hours postoperatively.

Postoperative management
Postoperatively, all animals remained fully sedated (fentanyl 25 µg · kg^-1 · h^-1, midazolam 0.2 mg · kg^-1 · h^-1), paralyzed (pancuronium 0.2 mg · kg^-1 · h^-1), intubated, and monitored (arterial pressure, heart rate) continuously for 12 hours after surgery. At this time chest tubes were removed, infusions discontinued, and the animals weaned from ventilator and extubated.

Data collection
Magnetic resonance spectroscopy
Phosphorus 31 magnetic resonance spectra were acquired on a spectrometer built by the Francis Bitter Magnet Laboratory at the Massachusetts Institute of Technology (MIT) with the Oxford horizontal-bore 4.7 T magnet and surface coil. Each spectrum was the average of 128 acquisitions (1,024 complex data points, repetition rate of 4.65 seconds, spectrum width 5,000 Hz). Total acquisition time was 10 minutes. Peak areas of inorganic phosphate, creatine phosphate, and beta-nucleoside triphosphate were determined by Lorentzian curve fitting and peak integration (NMRI Software, New Methods Research, East Syracuse, NY). Changes in ATP concentration were assessed from the beta-nucleoside triphosphate peak area. The inorganic phosphate, creatine phosphate, and ATP data are reported as percentage of the baseline obtained over 10 minutes before the initiation of CPB. The pHi in the brain was calculated from the chemical shift of the inorganic phosphate peak relative to the creatine phosphate peak. Details of methods employed have been described previously [4, 5].

Near-infrared spectroscopy
The optodes transmitted and detected laser light at four near-infrared wavelengths (776 nm, 828 nm, 848 nm, and 913 nm) and connected to a near-infrared spectrometer (NIRO-500, Hamamatsu Photonics KK, Hamamatsu, Japan), which calculated concentration changes in HbO₂, Hb, total hemoglobin (tHb), and CytOx. These data were recorded continuously every 30 seconds from the initiation of anesthesia induction until 3 hours after the termination of CPB.

Neurologic evaluations
Neurologic and behavioral evaluations were performed at 24-hour intervals. Neurologic scoring data were adapted from the neurologic deficit score (NDS) and overall performance category (OPC) scale developed at the University of Pittsburgh [7, 8]. In the NDS system, a score of 100 was assigned to each of five general components (central nervous system function, respiration, motor and sensory function, level of consciousness, and behavior). A total score of 500 indicates brain death, whereas a score of 0 is considered normal. The OPC score assessed outcome in five categories: 1 = normal, 2 = moderate disability, 3 = severe disability, 4 = coma, 5 = brain death. NDS and OPC determinations were agreed upon by two members of the laboratory team blinded to the perfusion strategies. All animals were observed closely for seizure activity.

Histologic evaluations
The brain of the animal was fixed with perfusion of 4% paraformaldehyde on postoperative day 4. Histologic changes of the brain were evaluated by a pathologist who was unaware of the experimental procedure. After fixation, the brain was cut into eight to ten coronal slabs that were embedded in paraffin. Seven micrometer sections were stained with hematoxylin-eosin. A standardized list of 24 of the major gray and white matter structures was examined following the nomenclature for porcine neuroanatomy. The structures were scored according to their location within three broad categories (neocortex, hippocampus, and caudate) as described by Yoshikawa [9]. Histologic changes were rated on an arbitrary scale: 0 = no damage, 1+ = isolated damaged neurons, 2+ = small clusters of damaged neurons, 3+ = large cluster of injured neurons, 4+ = completely damaged neurons, and 5+ = frank cavitated lesions with necrosis.

Statistical analysis
The two experimental studies analyzed were performed according to exactly the same surgical protocol by the same surgeon (T.S.). Data acquisition was performed in the same fashion using the same devices. Furthermore, the original data were accessible for every experiment. Given these circumstances, we are of the opinion that we can treat the two experiments as one to increase the statistical power for the analyses.

All results were analyzed by a statistical analysis software package (SPSS for Windows, Version 7.0, SPSS Inc, Chicago, IL). Parametric correlation coefficients according to Pearson were calculated to analyze the MRS and NIRS data. Nonparametric correlation coefficients according to Spearman were used for the correlation analyses of the abovementioned parameters with the NDS, OPC, and histologic score. A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Course of near-infrared and magnetic resonance spectroscopic parameters
The parameters showed different characteristics during the cooling phase. HbO₂, PCr, and pHi increased significantly, whereas ATP and CytOx decreased. During DHCA all parameters showed a decline. PCr was not detectable at the end of DHCA. After the onset of reperfusion all parameters recovered to baseline values and in part exceeded those (PCr, HbO₂). Figures 1 and 2 show the courses of NIRS and MRS parameters during the experiments in detail.

View larger version (27K): [in this window] [in a new window]   Fig 1. Time course of adenosine triphosphate (ATP), phosphocreatine (PCr), and intracellular pH (pHi) during the experiments. ATP values are slightly reduced during cooling and drop with the onset of deep hypothermic circulatory arrest (DHCA). ATP values decrease further without reaching a plateau and increase again with rewarming. PCr and pHi values rise with the beginning of cardiopulmonary bypass (CPB). Both parameters decrease quickly during DHCA with PCr storages becoming depleted after 30 minutes of DHCA. With reperfusion PCr and pHi increase and exceed baseline values. (CytOx = oxidized cytochrome a,a3; DPF = differential pathlength factor; HbO2 = oxygenated hemoglobin.)

View larger version (24K): [in this window] [in a new window]   Fig 2. Time course of oxidized cytochrome a,a3 (CytOx) and oxygenated hemoglobin (HbO2) during the experiments. CytOx values decrease with the onset of cooling and drop with the start of deep hypothermic circulatory arrest (DHCA). They continue to decrease slowly during arrest and reach a plateau at 20 minutes. They increase with rewarming and reperfusion and exceed baseline values at the end of cardiopulmonary bypass (CPB). HbO2 values increase with the onset of cooling on CPB. Deoxygenation takes place immediately after beginning of DHCA. HbO2 rises after start of reperfusion and exceeds baseline values. (ATP = adenosine triphosphate; PCr = phosphocreatine; pHi = intracellular pH.)

View larger version (19K): [in this window] [in a new window]   Fig 3. Neurologic damage. Postoperatively the piglets were neurologically examined daily by two persons. Sixty minutes of deep hypothermic circulatory arrest produced deficits in the neurologic deficit score (NDS; 0 = normal; 500 = brain death) and in the overall performance categories (OPC; 1 = normal; 5 = brain death), which were mild and most pronounced on the day of extubation (first postoperative day [POD 1]). On POD 4 the piglets had recovered completely.

View larger version (13K): [in this window] [in a new window]   Fig 4. Histopathologic brain damage. After perfusion fixation on postoperative day 4 defined brain regions were analyzed by light microscopy. For assessment a qualitative score system was used: 0 = no damage, 1+ = isolated damaged neurons, 2+ = small clusters of damaged neurons, 3+ = large cluster of injured neurons, 4+ = completely damaged neurons, 5+ = frank cavitated lesions with necrosis. The highest score in a region is shown. On average 60 minutes of deep hypothermic circulatory arrest caused only mild brain damage.

View larger version (23K): [in this window] [in a new window]   Fig 5. Correlation between intraoperative magnetic resonance spectroscopic (MRS) and near-infrared spectroscopic (NIRS) measurements. Forty piglets underwent 40 minutes of cooling, 60 minutes of deep hypothermic circulatory arrest at 15°C, and 45 minutes of rewarming. Changes in brain adenosine triphosphate (ATP) (A) and phosphocreatine (PCr) (B) were determined by MRS every 10 minutes during cardiopulmonary bypass and correlated to changes in the oxidized cytochrome a,a3 (CytOx) NIRS signal. Changes in the high energy phosphates are measured and expressed as percent of baseline values. The variation in the cytochrome signal is described as a change from baseline values in relative chromophore concentration. The value for every measurement at a specific time is shown as mean and standard error of mean. CytOx showed the highest correlation to PCr changes and also demonstrated significant correlation to ATP and intracellular pH variations (see Table 1). (DPF = differential pathlength factor)

View larger version (21K): [in this window] [in a new window]   Fig 6. Correlation between adenosine-triphosphate (ATP) and oxidized cytochrome a,a3 (CytOx) measurements and neurologic outcome. On postoperative day 4 the brain of the animal was fixed with perfusion of 4% paraformaldehyde. Histologic changes were rated on an arbitrary scale (see Material and Methods). The most severe injury in a brain region of an animal was correlated to the minimum values of CytOx (A) and ATP (B) recorded during the operation. All animals with visible structural brain damage had shown severe changes in the CytOx signal and—less pronounced—the ATP signal. Correlation coefficients are shown in Table 2. (DPF = differential pathlength factor.)

	Comment

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The validity of monitoring cerebral oxygenation at a cellular level by measurements of the cytochrome aa₃ signal with a NIRS machine that does not give absolute values has been doubted [13, 14]. The pathlength of near-infrared light in brain tissue is influenced by factors such as optode placement, age of the patient, geometry of the skull, brain temperature, edema, and pH. Some of these factors certainly change during our experiments and may even have a different influence on every single wavelength used for the calculation of the CytOx signal. In addition, the Hamamatsu device (NIRO-500) detects only the change in redox state, but not the absolute value of the redox state. Therefore, the detected correlation between the CytOx values and outcome could be influenced strongly by the changes in pathlength and the scattering properties of the brain. However, a major change in pathlength itself could be an indicator of brain damage. Therefore, it remains uncertain whether a reduction in the CytOx value reflects a decrease of cerebral CytOx or just a change in pathlength, but as is demonstrated in this study, it does indicate brain damage.

Clinical validation of the near-infrared spectroscopic signal
NIRS technology has been applied in various clinical fields such as neonatology, neurosurgery, and cardiac surgery. It has been used to monitor cerebral oxygenation during cardiac or vascular surgery associated with DHCA. Impaired cerebral oxygen metabolism has been detected by decreased CytOx [15, 16]. Although the correlation between NIRS data and neuropsychologic deficits after cardiac surgery should be strongly assumed, data are very limited [17, 18]. The CytOx signal has been validated in a clinical study showing high correlations to factors of operative management, eg, pH, pCO₂, hematocrit, and temperature [19].

Correlations between near-infrared and magnetic resonance spectroscopic data
This metaanalysis of two experimental studies has revealed important correlations between CytOx and nucleoside triphospate, PCr, and pHi. These results are consistent with a previous study from our institution demonstrating this relation in piglets submitted to different stages of hypoxia [3]. We hypothesized that the relation between high energy phosphates and CytOx values might not be linear. However, assumption of a linear curve fit revealed the highest correlation when compared with other nonpolynomial curves. The values for Hb and tHb showed poor correlation to MRS data. In comparison to the CytOx measurements, HbO₂ values showed similar, but lower correlation to high energy phosphates.

Correlations between near-infrared and magnetic resonance spectroscopic data and histology
The lowest CytOx value recorded during DHCA proved to be a highly sensitive predictor of histologic brain damage as assessed by light microscopy after 4 days. The predictive value of CytOx was much higher than that of ATP. It is reasonable to assume that a combination of the level and the duration of hypoxia/ischemia causes brain damage. However, the minimum CytOx value was a better predictor for neurologic damage than the average CytOx value during DHCA, duration of reduced CytOx values, or the integral of decreased CytOx values over time. This indicates that there might be a threshold of brain deoxygenation and only the duration of severe ischemia/hypoxia exceeding this deoxygenation threshold causes injury.

Other NIRS factors such as HbO₂ and Hb failed to show any correlation with histology. This finding supports the thesis that the value of these signals during episodes of increased oxygen affinity to hemoglobin because of hypothermia and alkalosis is doubtful. As these signals are highly related to the brain venous saturation [20], it had been assumed that they provide an index of the adequacy of global cerebral oxygenation [21]. A theoretical approach by computer modeling as well as clinical and experimental findings led to the hypothesis that high regional tissue oxygen levels estimated by NIRS values during CPB might indicate decreased offloading of oxygen from hemoglobin and not necessarily adequate tissue oxygenation [4, 15, 17, 19, 22].

Conclusion
This study indicates that the CytOx signal measured by the NIRO-500 spectrometer might be a better predictor for neuronal damage than cerebral high energy phosphates. In addition, NIRS monitoring is noninvasive, continuous, cost effective, and applicable during operation. It may become the method of choice in brain monitoring during DHCA to predict the safety limit of circulatory arrest.

	Acknowledgments

 
We are very grateful to Miles Tsuji, MD, Department of Neurology, St Joseph’s Hospital, Wisconsin, and David H. Holtzman, MD, PhD, Department of Neurology, Children’s Hospital Boston, for a critical review of the paper and their thoughtful suggestions.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Georg Nollert Dominique Shum-Tim Richard A. Jonas Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shin’oka, T. Articles by Jonas, R. A. Search for Related Content PubMed PubMed Citation Articles by Shin’oka, T. Articles by Jonas, R. A.