Effect of intermittently raised intracranial pressure on breathing pattern, ventilatory response to CO2, and blood gases in anesthetized cats SHEILA JENNETT,M.D., PH.D., AND J. BRIAN NORTH, F.R.A.C.S.
Departments of Physiology and Neurosurgery, Universityof Glasgow, Scotland In anesthetised cats, breathing pattern, blood gases, and ventilatory response to CO2 were recorded before and during intermittent 10-minute episodes of hydrostatically raised intracranial pressure. The first effect on breathing was a stimulation which was followed at higher pressures by irregularity, depression, and periods of apnea; hyperventilation at high intracranial pressure (ICP) was rare. Raised ICP did not consistently depress the ventilatory response to CO2 until ventilation during airbreathing was already depressed; therefore, we cannot experimentally justify applying this test clinically to detect incipient ventilatory depression. When hypoxemia developed during raised ICP, it was compatible with the degree of hypoventilation due to central depression of breathing; thus, there was no evidence of a neurally mediated effect on the lungs, causing defective gas exchange. KEY WORDS hypoxemia
respiratory depression 9 intracranial pressure 9 9 ventilatory response to C02 9 cardiovascular responses 9
ONSIDERABLEdiscrepancies exist in the reported effects of raised intracranial pressure (ICP) on respiration; such effects include those on breathing pattern, ventilatory control, and pulmonary gas exchange. In 1902, Cushing 5 referred to both stimulation and depression of breathing; recent reports have described consistent stimulation, a,2~ consistent depression, a2 and various combined or inconsistent findings, a6,~Ta~ Some of the discrepancies clearly stem from differences in species and in method: for example when, as in most studies, pressure is raised by inflation of balloons ~,ga~or by cold lesions ~,~e the effects of brain-stem distortion cannot be separated from those of raised ICP
c
per se. Hydrostatic methods of raising pressure are more likely to allow this distinction and thus perhaps assist the clinical appraisal of particular ventilatory disturbances as indications of raised pressure. It has been suggested 4 that depression of the ventilatory response to carbon dioxide might precede overt respiratory changes when ICP is raised; this might be useful in diagnosis or prognosis. Alterations in responsiveness to CO2 have been described in various types of brain damage, but usually when there are also manifest abnormalities of breathing? 6,27 Hypoxemia is commonly observed in association with head injury and other types of acute brain damage. There has been some
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C h a n g e s w i t h i n t e r m i t t e n t l y raised I C P in cats experimental ~'32 and clinical 3 support for the hypothesis that there is a neurally mediated effect on the pulmonary vasculature which causes an increase in venous admixture, and leads to degrees of hypoxemia; sympathetic stimulation in other experimental contexts, however, causes only improvement in pulmonary gas exchange? 8 We planned experiments in which these three aspects of respiration could be studied during increases of ICP produced hydrostatically. A preliminary report of this study has been made. ~4 Materials and Methods
Twenty cats were used, weighing 1.9 to 3.8 kg. They were anesthetized with intraperitoneal pentobarbitone (30 mg/kg) with later supplementary intravenous doses as required. The animals breathed spontaneously, and at the time of the experiment, arterial blood gases were in the normal range 8'~~of 26 to 34 torr for pCO~ and 85 to 106 torr for pO~. After tracheal and femoral arterial and venous cannulation, a lumbar laminectomy was performed and a cannula passed up alongside the spinal cord intrathecally for several centimeters. It was secured and sealed in by an extradural ligature which included the cord. A parietal burr hole was made and a cannula with multiple punctures at the tip was inserted into the subdural plane and the skull was sealed with dental acrylic. This cannula was attached to a pressure transducer and the output checked for normal pulsations: their presence, and an immediate rise of ICP in response to a small lumbar infusion, allowed repeated confirmation of free communication and patency, and indicated a valid ICP measurement. The following continuous measurements were established on a UV chart recorder (S.E. 2005): pressures from the intracranial cannula (ICP) and from the femoral artery (blood pressure) by photoelectric transducers calibrated in parallel against a mercury manometer; percentage of CO2 in inspiredexpired air from the tracheal cannula, for calculation of end-tidal pCO2 by rapid infrared analyzer calibrated by gas mixtures analyzed on the Lloyd Haldane apparatus; integrated inspired volume (V~) by pneumotachograph with a flow head attached to the tracheal cannula calibrated for flow rates of 2
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to 6 1/min by Rotameter, and being within 5% of linearity at the extremes of this range; instantaneous heart rate (HR), with the BP transducer output used to trigger a Devices ratemeter by an oscilloscope (CRO).* In addition to these continuous records, arterial blood was sampled intermittently, and immediately analyzed for pH, pCO~, and pO2 on the Radiometer system BMS1, calibrated by gas mixtures from a Wosthoff pump.t Measurement temperature was 37 ~ C and the values were corrected to the animal's rectal temperature at the time of each sample, with the Severinghaus blood-gas calculator.$ Mock CSF s~ was used at 37 ~ C for lumbar infusions to raise the ICP; infusion was controlled by hand from a 50-ml syringe, the ICP was raised by 1 mm/sec and then kept constant by watching the display from the ICP transducer on the CRO.
Method for Rising C02
Ventilatory
Response
to
Read's brief rebreathing method ~9 was used, with the technique developed in this
*UV chart recorder (S.E. 2005) manufactured by SE Lab (EMI) Ltd., North Feltham Trading Estate, Feltham, Essex, England. Photoelectric transducers manufactured by Mercury Electronics (Scotland) Ltd., Pollock Castle Estate, Newton Mearns, Glasgow, Scotland. Rapid infrared analyzer (URAS 2000) manufactured by Hartmann and Braun AG, Post Box 900507, Frankfurt, Main, West Germany. Lloyd Haldane apparatus manufactured by Gallenkamp & Co., PO Box 290, Technico House, Christopher Street, London EC2P 2ER, England. Computing Spirometer CS1 manufactured by Mercury Electronics (Scotland) Ltd., Pollock Castle Estate, Newton Mearns, Glasgow, Scotland. Rotameter manufactured by GEC-Elliott Process Instruments Ltd., Rotameter Works, 330, Purley Way, Croydon CR9 RPG, England. Devices ratemeter manufactured by Devices Instruments Ltd., Welwyn Garden City, Herts, England. CRO oscilloscope manufactured by Tektronix Guernsey Ltd., Guernsey, Channel Islands, England. tRadiometer system BMS1 manufactured by Radiometer A/S Emdrupvej, 72 DK 2400, Copenhagen, Denmark. Wosthoff pump manufactured by H. Wosthoff, Buchum, Germany. ~Severinghaus blood-gas calculator manufactured by Radiometer A/S Emdrupvej, 72 DK 2400, Copenhagen, Denmark. ]57
S. Jennett and J. B. North secutive 10 seconds. When these values were plotted in earlier experiments, no consistent relationship other than a linear one was suggested. Subsequently the regression of ventilation on pCOs was calculated by the method of least squares, and when the correlation coefficient was greater than 0.8 the Fx~. 1. Rebreathing apparatus for determination of ventilatory response to rising COs. Animal relationship was accepted as linear; the breathes in and out ofa polythene bag contained in parameters of the regression equation gave a Perspex cylinder. the slope (S) of the response of ventilation to COs and the intercept representing pCOs at zero ventilation (Fig. 2).
Procedure When all recordings were established and baseline blood gases had been measured and found to be acceptably normal, a series of increases in ICP was imposed, each lasting 10 min and each successively 10 mm Hg higher (Fig. 3). Earlier experiments showed that there was rarely any effect on respiration at ICP lower than 50 mm Hg, so this was used as the first pressure. Pressure was always increased at the same rate of 1 mm Hg/sec as smoothly as possible within the limits of manual control. At the end of each 10-min period ICP was allowed to fall, and recovery FIG. 2. Ventilatory response to COs: solid line of the several recorded variables was allowed shows mean slope (S =/xVI/ApCO~) .extrapolated to mean intercept (pCO~ at zero V~) from before the next episode of raised ICP. repeated tests on 10 animals at normal ICP; broken lines indicate the range of slopes found. S Timing of Blood Gas Measurements and was calculated from the linear regression of ven- C02-Response Tests tilation on pCO2 using values for consecutive 10Blood was taken immediately before a second periods during rebreathing. pressure rise, and during the fifth minute at high ICP. To avoid excessive depletion of the blood volume, samples were taken in alternate pressure runs only. The CO2-response laboratory for human subjects, scaled down to appropriate dimensions. The tracheal can- tests were carried out in a similarly paired fashion before and during every high-pressure nula was attached to a polythene bag filled run: the baseline test was between I0 and 5 with approximately 100 ml 5% COs in oxygen, and contained within a Perspex cylinder minutes before the run and the high ICP test was applied just after the arterial blood was sealed except for an attachment to a flow sampled, after 5 to 8 minutes of high ICP head, and sampling and return tubes for COs (Fig. 3). analysis (Fig. 1). Thus, ventilation could be The first 10 cats were used to provide data recorded continuously during the rebreathing for breathing pattern, BP, and blood gas by a bag-in-box method. changes only; in the second 10 cats the venDuring such rebreathing from a gas mixtilatory response to CO2 was also studied. ture with the percentage of COs initially near to the mixed venous pCO2 value, there is a Anesthetic Level brief equilibration period followed by a linear rise in COs and normally a progressive inBy careful reference throughout to the concrease in ventilation. In every test the period tinuous records of end-tidal pCOs, ventilaof this linear rise was defined, and the values tion, and BP, the depth of anesthesia was kept for pCO2 and ventilation found for each con- near constant; supplementary doses were suf158
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Changes with intermittently raised ICP in cats
Fic. 3. Experimental protocol. Each increase of intracranialpressure was maintained for 10 minutes and recovery allowed before the next. All animals were exposedto the levels shown up to 120 mm Hg ICP; some survived to higher levels (broken arrow). Timing of blood gas measurements (arrows) and rebreathing tests (bars) is shown, before and during runs of raised ICP.
ficient only to restore these variables to baseline; paired normal and raised ICP measurements were not started until or unless the animal's state was stable. Results
Ventilation and Pattern o f Breathing In nearly all animals, the first effect observed on the breathing was stimulation. This tended to occur during a rise of pressure; then, as pressure was held constant, hyperventilation might persist, or, at the higher pressures, give way to irregularity, depression, and periods of apnea; there was quite frequently a relative recovery from depression after the first 1 or 2 minutes at pressure; distinct periodicity occurred in less than half the animals. The disturbances became progressively more severe with successively higher pressure levels, until there was apnea with recovery only after release of pressure, and ultimately irreversible apnea. The range of ICP at which these several effects occurred in different animals was very wide: this was partly attributable to variations both in the initial arterial blood pressure and in the extent of the rise in BP when ICP was raised: there was less scatter of threshold values for depression and apnea in terms of cerebral perfusion pressure (CPP, mean B P - mean ICP) (Fig. 4). Persistent apnea occurred at perfusion pressures which still allowed maintained vasomotor activity, as evidenced by the persistence of a raised BP. In one exceptional animal ventilation was consistently stimulated at an ICP of 150 and
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FIG. 4. Threshold ICP values for each effect on ventilation: range (solid lines) and mean (0). Threshold CPP (mean BP - mean ICP) for each effect: range (broken lines) and means (0). The range of threshold values causing ventilatory depression and apnea is smaller for CPP than for ICP. No mean is shown for CPP related to irreversible apnea because at this stage CPP was very variable, due to large swings in BP.
CPP of 27 mm Hg; only at ICP 160 mm Hg was the initial stimulation followed by depression, and apnea occurred at 170 mm Hg. When ventilation was stimulated, there was commonly an increase in both frequency and 159
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FIG. 5. Records showing the several recorded variables during release of raised ICP ( ~ 100 mm Hg) at the end of 10 rain. Starting from the top: Airway percentage of COs (the scale is linear, with the zero offset beyond the UV paper): End-tidal level represents pCO~ of 29 to 30 torr. In this and other experiments, end-tidal and arterial pCO2 values were normally not more than 5 torr different unless tidal volume was exceptionally small. HR = heart rate. BP = arterial (femoral) blood pressure. ICP = intracranial pressure, held within 8 mm Hg of 100; fluctuations followed those of BP. Cumulative inspired volume showed a 30-sec volume of 140 to 150 ml, that is, a ventilation of 280 to 300 ml/min. VT = tidal volume. Note that there had been no significant alteration in minute volume, breathing pattern, or arterial blood gases during this run, although a small change in pattern can be seen after release of pressure. The CPP was 45 to 50 mm Hg: this animal's threshold CPP for ventilatory depression was at the low end of the range shown in Fig. 4. There had been a considerable increase in BP, and a small increase in HR; both are shown returning to baseline. The ICP of 95 to 100 mm Hg, which had been maintained for 10 minutes, was 15 to 20 mm Hg above the animal's baseline diastolic BP.
FIG. 6. Record showing irregularity and depression of ventilation at ICP 100 and CPP ~60 mm Hg. Large falls in BP related to breaths. Traces are as in Fig. 5. PaCO2 = 42 tort and PaO2 = 69 torr during this run (compare with Fig. 8). This animal's threshold CPP for ventilatory depression was at the high end of the range shown in Fig. 4. 160
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C h a n g e s w i t h i n t e r m i t t e n t l y raised I C P in cats tidal volume, but the pattern was not consistent. Depression, however, always entailed a reduction in frequency, with irregularity both of cycle length and of tidal volume. Blood Pressure Changes The arterial BP almost always increased, even with the lowest intracranial pressures applied. The ICP threshold for this response of BP was most often lower than that for the first effect on breathing: in no animal was it higher (Fig. 5). The pressure to which an animal survived was not related to its initial BP; since apnea eventually occurred at perfusion pressures below 30 mm Hg, it follows that the higher the BP response achieved, the higher was the ICP attained before apnea supervened. At the highest ICP levels in each animal, those associated with ventilatory depression and irregularity, BP increased dramatically (in some up to 100% above baseline level), and this was followed by large irregular oscillations as well as a much increased pulse pressure. Ventilation was erratic at this stage, and large gasping breaths were followed immediately by steep reductions in BP (Fig. 6). These latter observations at high pressures were consistent with many earlier investigations; however, the increases in BP at lower ICP's differ from the findings of some authors, such as Weinstein, et al? 4 Results are presented and discussed in detail elsewhere. 15 Heart Rate Changes
Ventilatory Response to Rising C02 Variation in the parameters of the response was considerable, not only between animals, but also in any one animal. Because of variations associated with minor fluctuations in anesthetic level and body temperature, values were compared before and during each individual high-pressure run and each change expressed as a percentage. Even so, separation by about 15 minutes could account for considerable random differences in the slope of the CO2-response line (S). In two animals studied as controls, without increases in ICP, the variation in S was similar to the variation between responses at normal ICP in the experimental animals. Examples of paired values for three experimental animals and one control animal are shown in Fig. 7. No change was consistently attributable to raised ICP until or unless there was clear interference with breathing pattern and ventilatory depression breathing air. In most animals there were two or three penultimate levels of high ICP at which the response to COs was lost, and at which there was gross irregularity of breathing, yet from which recovery was complete within 3 to 5 minutes of release of pressure after the 10-minute exposure. The values for intercept were treated similarly to those for slope, and did not show any consistent effect attributable to pressure in advance of ventilatory depression. Intercept was a less variable value than slope. There was no tendency for this value to increase with raised ICP.
The earlier, less dramatic, increases of BP Arterial Blood Gases were usually accompanied by small increases in HR. Only the later steep increases were Paired values before and during high ICP associated with decreasing HR (Fig. 6). Large runs showed no changes other than those swings of heart rate sometimes accompanied related to varying anesthetic level, until venthe infrequent very deep gasping breaths of tilatory depression occurred: there were small severe respiratory depression. As in normal changes in PaCO~ accompanied by changes in sinus arrhythmia, an increase in H R began PaO2 in the opposite direction, and of an apwithin 1 second of the start of inspiration; in propriate extent. The predicted PaO2-PaCO2 one animal only, we saw an increase in the relationship for cats under pentobarbitone amplitude of respiratory sinus arrhythmia anesthesia was defined by pooling data from which was not attributable either to a reduc- 28 animals breathing air, at normal ICP, tion in mean heart rate or to an alteration in from this and an earlier series. Points were breathing pattern. We could not confirm in plotted on a pO2-pCO2 diagram 28 (Fig. 8). this series the suggestion that there may be a The overall mean values at normal ICP consistent specific effect of raised ICP on the were PaO2 97.9 torr and PaCO2 30.3 torr. amplitude and the time-course of sinus The mean PaO2 for all raised ICP runs was arrhythmiag ,8 91.6 torr and PaCO2 33.7 torr; for this J. Neurosurg. / Volume 44 / February, 1976
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F~. 7. Pairs of values for the ventilatory response to rising CO2 during rebreathing. Each slope represents the linear regression line calculated from data for ventilation and pCO2 in the manner described in the text, and Fig. 2. A slope of 45 ~ is equivalent to an increase of 100 ml/min/unit increase in pCO2. The top three sets are from three of the experimental animals. The solid lines show the consecutive values for S measured at normal ICP, before each experimental increase in ICP. The broken lines show the values for S during raised ICP, at the levels shown beneath each pair of slopes. The pairs of estimations before and during the smaller increases in ICP show a random difference attributable to the error of the method and small variations in depth of anesthesia; X at the highest ICP levels indicates that there was not any significant response to CO2: ventilatory depression breathing air was already evident at these pressures and at the one or two penultimate levels at which S was diminished. The lowest set of values is from a cat studied over a comparable period with similar anesthesia. In all these animals, S changed inversely with end-tidal pCO2, whether the variation in the latter was related to minor variations in depth of anesthesia, or to ventilatory depression at high ICP.
minimal degree of hypoxemia to be attributable to hypoventilation, PaO2 should be similar to the value at the coexisting PaCO2 predicted from the relationship defined at normal ICP: the predicted value is 91.7 torr. Four animals appeared to show a disproportionate hypoxemia at their highest ICP; however, similar reduction in PaO2 could be brought about at normal I C P when ventilation was depressed by increments of pentobarbitone (Fig. 8). "162
Discussion
Method o f Increasing ICP We chose a hydrostatic method in order to avoid the complicating effects of brain shift and herniation, and of supra- and infratentorial pressure differences; an earlier unpublished series of experiments in eight cats had indicated that raising I C P by subdural balloon inflation led to very inconsistent
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Changes with intermittently raised ICP in cats effects on breathing, and entailed difficulties in maintaining steady pressures and in measuring confidently the relevant ICP; some animals failed to recover completely from 10 minutes at relatively low pressures by the balloon method, while lumbar infusion could be applied repeatedly and to quite high levels in many animals, with complete recovery between runs. Many reported series have employed prolonged, progressively rising or stepwise increases in ICP. We chose intermittent increases lasting only 10 minutes and compared the several measurements with values found FIc. 8. Black circles indicate data from 28 immediately preceding that pressure rise; thus, any effect would have been seen which animals at normal ICP breathing air under pentobarbitone anesthesia; solid line is the regression was a direct or reflex result of that pressure, line. Broken line is the comparable regression line rather than its more indirect, delayed, or for values (not shown) for all cats at all levels of cumulative effect. Also, waves of increased raised ICP. Open circles are values during the pressure are common clinically, and often of most severe ventilatory depression during raised ICP, from each of 11 cats. Crosses show values comparable duration, so this model may from each of two cats when ventilation was more nearly imitate real conditions than the depressed by increments of pentobarbitone. imposition of continually rising or maintained pressure. The rate of rise of pressure was kept constant for all animals and all ICP levels so that differing effects due to varying rates of rise at the highest levels. Such rises in BP necessarily entail a large increase in symwere excluded. pathetic outflow." This is relevant when one considers the possibility of any sympathetic Perfusion Pressures effect on the pulmonary vascular bed. We are Many investigators have chosen to apply a satisfied that we were studying in these exconstant level of ICP, or to impose a level periments a condition in which there was inrelated to each animal's initial arterial BP. deed an increase in sympathetic activity. We have confirmed the numerous obserOur experience emphasized that any one level of ICP was far from comparable from one vations that when ICP rises, respiratory animal to another, because of variation in ini- center activity ceases before vasomotor actial BP and in the animals' BP response. To tivity; however, it is possible that the compare animals we estimated the perfusion vasomotor response might have been mainpressure, calculated conventionally as mean tained in part by the effect on spinal centers arterial BP minus mean ICP. However, this of raised pressure, la,3~ does not make experiments comparable in terms of medullary blood flow, since the state Response to Rising C02 of cerebral vasodilatation at any one perfuThe ventilatory response to COs did not sion pressure varies between animals. usually show any significant change in any We have shown that severe ventilatory one animal until ventilatory depression was depression generally occurs at a CPP below already evident. 40 to 60 mm Hg, which is regarded as the There was a suggestion that the response level below which CBF is no longer unwas diminished at a slightly lower ICP than changed by vasodilation. 19'a5 the level causing ventilatory disturbance, but it was not significant enough to suggest a Sympathetic Activity useful application in detecting imminent venThe magnitude of the BP response was tilatory disturbance clinically. The interpretacommonly progressive with increasing ICP tion of the effects of COs breathing is comand was always considerable (30% or more) plex since it provokes not only a ventilatory
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S. Jennett and J. B. North but also a cerebrovascular response which further increases the ICP when it is not deliberately kept constant as in these experiments. Our results of such tests in patients are reported elsewhere. 23 The decline in response to CO2 pari passu with the development of hypoventilation on air, would be consistent with depression either of respiratory neurons themselves, or of central chemoreceptors.
Breathing Pattern The stimulation of breathing during pressure rise seems to occur in some patients during spontaneous increases of ICP. 24 It could be a direct and specific effect of pressure, but if so, would be unlikely to pass off after the initial rise, as it did in many animals; a stimulation of breathing has been noted during localized pressure on the brain stem. ~s Alternatively, an initial reduction in blood flow, with increase in acidity around the medullary chemoreceptors, might be returned to normal as local vasodilatation occurs. Chemical effects of the infused fluid on the surface of the spinal cord or medulla are unlikely to have accounted for the ventilatory changes, because of the absence of such effect during infusion at pressures lower than each animal's "threshold" ICP. We rarely saw persistent hyperventilation at high ICP, as that reported in approximately 50% of rabbits '7 and in all cats after cold lesions. ~ In these latter experiments, it was reported that a phase of periodicity was followed by rapid respiration, a sequence which we never saw. The example of tachypnea shown consists of regular breathing at a frequency of 25/min, which is about normal, in our experience, for anesthetized cats (Fig. 5). The absence of blood gas values also makes it difficult to know whether there was a true hyperventilation. Increased ventilation at high ICP has also been reported in dogs ~ but the situation was complicated by hypoxemia. The depression of ventilation which occurred with diminishing perfusion pressure was consistent with a great many observations by others. This disturbance has usually been attributed to local hypoxia due to brain-stem ischemia. In models in which pressure is raised asymetrically and supratentorially, distortion might readily account
16d
for such an effect; in hydrostatically raised pressure, with evidence of free communication between compartments, this factor would appear to be excluded. The direct, symmetrical effect of pressure or some indirect effect on the respiratory center must be held to account. Ventilation was often partly inhibited at perfusion pressures in the range of 40 to 60 mm Hg; such perfusion pressures during raised ICP (in other species) are reaching the point at which cerebral vasodilatation fails to maintain blood flow at its normal value. 19,3s Therefore, CPP in this range is unlikely to be associated with less than 70% to 80% of normal blood flow. Since ventilatory depression by systemic hypoxia does not occur until the PaO2 falls as low as 20 to 30 torr, it seems unlikely that the reduced oxygen delivery in an undistorted brain stem, during our conditions of raised ICP, would cause a sufficient decrease in tissue pO2 to depress the breathing. But the local capillary blood flow might be peculiarly vulnerable. Perhaps a failure of stimulation, or an inhibitory influence on the respiratory neurons from another site should be considered.
Arterial Blood Gases Such hypoxemia as we found in these experiments appears to be explicable without invoking any effect of ICP on the lungs themselves. We have explained the reasons for regarding the PaO~ values as related simply to the central depression of breathing, with hypoventilation and hypercapnia. Other investigators have reported hypoxemia without raised PaCO2 at high ICP, notably in dogs: either a reduction in PaO2 breathing oxygen2 or an actual hypoxemia breathing air. 21 The initial arterial pO2 values were below normal in both series, which suggests a significant pre-existing shunt or ~la/O imbalance, against which background the raised ICP effect is difficult to assess. The discrepancies might represent a species difference. However, other experiments on dogs have not shown hypoxemia. 25 It might be suggested that the difference is one of duration. If we had maintained high ICP for longer, hypoxemia might have developed: Berman and Ducker 2 report a "progressive" hypoxemia. However, if the effect is attributable to sympathetic activity, we would expect to see it at the height of such activity, at high pressures which invoke a large BP
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Changes with intermittently raised ICP in cats response. At such pressures, the hypoxemia in our cats was again only equivalent to the extent of ventilatory depression. From our experience in these studies we have become aware of certain criteria which must be fulfilled before hypoxemia can be attributed to an effect of high ICP on the lungs. Attention must be paid to correction of pO2 values for body temperature which may be difficult to control; the predicted decrease in pO2 for a given increase in pCO2 for the particular species and anesthetic must be known, so that changes related to hypoventilation can be properly assessed; the arterial blood gases must be normal in the baseline conditions because otherwise hemodynamic changes associated with raised ICP may, on the background of existing abnormality, cause alterations in venous admixture which could be confused with a primary effect of pressure; the arterial blood gases should return to normal once the pressure is released. Within these criteria, we have been unable to demonstrate a hypoxemic effect. Clearly there are many other ways in which acute brain damage in general, and raised ICP in particular, can be associated with arterial hypoxemia, is One such situation is the occurrence of pulmonary hemorrhage and edema, from which the proposed mechanism for production of hypoxemia is to be distinguished. 2 In our view the evidence for a neurally mediated effect on the lungs causing hypoxemia is not yet convincing, and the further step to treatment by sympathetic blocking agents 3,2~ could interfere with compensatory mechanisms.
Effect o f Anesthesia The results from this series of cats under pentobarbitone anesthesia may not be applicable to other species, other anesthetic agents, or to awake animals or man. Some differences from other series may be related also to the depth of anesthesia. The low threshold for BP response and the occurrence of stimulation of ventilation may have been because our animals were kept at a level which maintained a near-physiological pCO~ (around 30 torr), rather than the somewhat higher values often reported. Within the series, and within each animal, care was taken to distinguish the effects of changing depth of anesthesia from those of raised ICP.
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Conclusion
We have demonstrated that, in anesthetized cats, when ventilation is depressed by raised intracranial pressure, the alterations in blood gases and in ventilatory responsiveness to increasing CO2 are related to the extent of the hypoventilation; the changes are similar to those which occur with increasing depth of anesthesia. There is, thus, no need to postulate a specific effect of increased ICP on pulmonary gas exchange. Acknowledgments
We acknowledge the benefit of suggestions and discussion by Drs. J. T. Hoff and J. D. Miller, and of technical assistance by G. Burnside and Alexis Young. References
1. Beks JWF: Effects of increased supratentorial pressure in cats. J Neurol Neurosurg Psychiatry 37:627-630, 1974 2. Berman IR, Ducker TB: Pulmonary, somatic and splanchnic circulatory responses to increased intracranial pressure. Ann Surg 169:210-216, 1969 3. Brackett CE: Respiratory complications of head injury, in International Symposium on Head Injuries. Edinburgh, Churchill Livingstone, 1971 (US distributors: Williams & Wilkins), pp 255-265 4. Briggs M, Adams AP" Ventilatory and intracranial pressure responses to CO2 stimulation. Br J Surg 60:315, 1973 5. Cushing H: Some experimental and clinical observations concerning states of increased intracranial tension. Am J Med Sci 124: 375-400, 1902 6. Dejours P, Lacaisse A: Arterial blood pH and partial pressures of O5 and CO2 in normal awake cats. J Physiol (Paris) 63:87-90, 1971 7. Fitch W, McDowall DG: Vasodilating anaesthetics and pressures in different compartments of the skull, in Brierley JB, Meldrum BS (eds): Brain Hypoxia. Philadelphia, London, W Heinemann Medical Books, 1971 (US distributor, JB Lippincott), pp l l3-117 8. Heck AF: Cardiorespiratory interaction during increased intracranial pressure, in Brock M, Dietz H (eds): Intracranial Pressure. New York/Heidelberg/Berlin, Springer-Verlag, 1972, pp 200-204 9. Heck AF: Cardiovascular and respiratory changes during transient increase in intracranial pressure, in Feischi C (ed): Cerebral Blood Flow and Intracranial Pressure. Basel, S
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S. Jennett and J. B. North 10. Herbert DA, Mitchell RA: Blood gas tensions and acid-base balance in awake cats. J Appl Physiol 30:434-436, 1971 11. Hoff JT, Mitchell RA: The effect of hypoxia on the Cushing response, in Brock M, Dietz H (eds): Intracraniai Pressure. New York/Heidelberg/Berlin, Springer-Verlag, 1972, pp 205-209 12. Hoff JT, Nishimura M, Pitts L: Effect of raised intracranial pressure on pulmonary function in cats, in Lundberg N, Pont~n U, Brock M (eds): Intracranial Pressure II. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 293-297 13. Hoff JT, Reis D J: Localization of regions mediating the Cushing response in CNS of cats. Arch Neurol 23:228-240, 1970 14. Jennett S, North JB: Breathing pattern, response to CO2 and blood gases in cats with experimental increases in intracranial pressure, in Lundberg N, Pont6n U, Brock M (eds): lntracranial Pressure II. New York/ Heidelberg/Berlin, Springer-Verlag, 1975, pp 311-314 15. Jennett S, North JB, Hoff JT: Two-stage blood pressure response to increased intracranial pressure in cats. (In preparation) 16. Kaste M, Troupp H: Effect of experimental brain injury on blood pressure, cerebral sinus pressure, cerebral venous oxygen tension, respiration, and acid-base balance. J Neurosurg 36:625-633, 1972 17. Kuurne T, Troupp H: Hydrostatically raised intracranial pressure. J Neurosurg 37: 695-699, 1972 18. Miller JD, Adams JH: Physio-pathology and management of increased intracranial pressure, in Critcheley M, O'Leary JL, Jennett B (eds): Scientific Foundations of Neurology. London, W Heinemann Medical Books, 1972, pp 308-324 19. Miller JD, Stanek AE, Langfitt TW: A comparison of autoregulation to changes in intracranial and arterial pressure in the same preparation, in Feischi C (ed): Cerebral Blood Flow and Intracranial Pressure. Basel, S Karger, 1972, pp 34--38 20. Moody RA, Ruamsuke S, Mullan S: Experimental effects of acutely increased intracranial pressure on respiration and blood gases: J Neurosurg 30:482-493, 1969 21. Moss IR, Lisbon A, Levine JF, et al: The effects of increased intracranial pressure on respiratory functions, in Lundberg N, Pont6n U, Brock M (eds): Intracraniai Pressure II. New York/Heidelberg/Berlin: SpringerVerlag, 1975, pp 315-318 22. Moss IR, Wald A, Ransohoff J: Respiratory functions and chemical regulation of ventilation in head injury. Am Rev Respir Dis 109:205-215, 1974 166
23. North JB, Jennett S: Cerebrovascular response pattern during rebreathing, in Langfitt TW, McHenry LC Jr, Reivich M, et al: Cerebral Circulation and Metabolism. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 249-250 24. North JB, Jennett S: The interpretation of simultaneous recordings in patients of breathing pattern and intracranial pressure, in Lundberg N, Pont6n U, Brock M: lntracranial Pressure II. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 460-463 25. Pitts LH, Severinghaus JW, Mitchell RA, et al: The role of increased intracranial pressure in the production of neurogenic pulmonary edema, in Lundberg N, Pont6n U, Brock M: lntracranial Pressure II. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 319-323 26. Plum F, Brown HW: The effect of respiration on central nervous system disease. Ann NY Acad Sci 109:915-931, 1963 27. Plum F, Brown HW: Hypoxic-hypercapnic interaction in subjects with bilateral cerebral dysfunction. J Appl Physiol 18:1139-1145, 1963 28. Rahn H, Fenn WO: A graphical analysis of the respiratory gas exchange: the O2-CO2 diagram. Washington DC, American Physiological Society, 1955 29. Read DJC: A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Meal 16:20-32, 1967 30. Rowan JO, Johnston IH: Blood pressure response to raised CSF pressure, in Lundberg N, Pont~n U, Brock M: Intracranial Pressure II. New York/Heidelberg/Berlin, SpringerVerlag, 1975, pp 298-302 31. Schlaefke ME, See WR, Loeschke HH: Ventilatory response to alterations of H § ion concentration in small areas of the ventral medullary surface. Respir Physiol 10:198-212, 1970 32. Staunton C, Stein AA, Moss G: Cerebral etiology of the respiratory distress syndrome: universal response, with prevention by universal pulmonary denervation. Surg Forum 24:229-231, 1973 33. Szidon JP, Fishman AP: Autonomic control of the pulmonary circulation, in Fishman AP, Hecht HH (eds): Pulmonary Circulation and Interstitial Space. Chicago, University of Chicago Press, 1969, pp 239-268 34. Weinstein JD, Langfitt TW, Kassell NF: Vasopressor response to increased intracranial pressure. Neurology (Minneap) 14:1118-1131, 1964 35. Zwetnow NN: Cerebral blood flow autoregulation to blood pressure and intracranial
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Changes with intermittently raised ICP in eats pressure variations. Seand J Clin Lab Invest Suppl 102:V-A, 1968
This work was supported in part by a grant to Dr. Jennett from the Scottish Hospital Endowments Research Trust.
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Dr. North was the recipient of a Commonwealth Medical Fellowship. Present address for Dr. North: Neurosurgical Clinic, Royal Adelaide Hospital, Adelaide, South Australia. Address reprint requests to: Sheila Jennett, M.D., Ph.D., Institute of Physiology, Glasgow G12 8QQ, Scotland.
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Departments of Physiology and Neurosurgery, Universityof Glasgow, Scotland In anesthetised cats, breathing pattern, blood gases, and ventilatory response to CO2 were recorded before and during intermittent 10-minute episodes of hydrostatically raised intracranial pressure. The first effect on breathing was a stimulation which was followed at higher pressures by irregularity, depression, and periods of apnea; hyperventilation at high intracranial pressure (ICP) was rare. Raised ICP did not consistently depress the ventilatory response to CO2 until ventilation during airbreathing was already depressed; therefore, we cannot experimentally justify applying this test clinically to detect incipient ventilatory depression. When hypoxemia developed during raised ICP, it was compatible with the degree of hypoventilation due to central depression of breathing; thus, there was no evidence of a neurally mediated effect on the lungs, causing defective gas exchange. KEY WORDS hypoxemia
respiratory depression 9 intracranial pressure 9 9 ventilatory response to C02 9 cardiovascular responses 9
ONSIDERABLEdiscrepancies exist in the reported effects of raised intracranial pressure (ICP) on respiration; such effects include those on breathing pattern, ventilatory control, and pulmonary gas exchange. In 1902, Cushing 5 referred to both stimulation and depression of breathing; recent reports have described consistent stimulation, a,2~ consistent depression, a2 and various combined or inconsistent findings, a6,~Ta~ Some of the discrepancies clearly stem from differences in species and in method: for example when, as in most studies, pressure is raised by inflation of balloons ~,ga~or by cold lesions ~,~e the effects of brain-stem distortion cannot be separated from those of raised ICP
c
per se. Hydrostatic methods of raising pressure are more likely to allow this distinction and thus perhaps assist the clinical appraisal of particular ventilatory disturbances as indications of raised pressure. It has been suggested 4 that depression of the ventilatory response to carbon dioxide might precede overt respiratory changes when ICP is raised; this might be useful in diagnosis or prognosis. Alterations in responsiveness to CO2 have been described in various types of brain damage, but usually when there are also manifest abnormalities of breathing? 6,27 Hypoxemia is commonly observed in association with head injury and other types of acute brain damage. There has been some
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C h a n g e s w i t h i n t e r m i t t e n t l y raised I C P in cats experimental ~'32 and clinical 3 support for the hypothesis that there is a neurally mediated effect on the pulmonary vasculature which causes an increase in venous admixture, and leads to degrees of hypoxemia; sympathetic stimulation in other experimental contexts, however, causes only improvement in pulmonary gas exchange? 8 We planned experiments in which these three aspects of respiration could be studied during increases of ICP produced hydrostatically. A preliminary report of this study has been made. ~4 Materials and Methods
Twenty cats were used, weighing 1.9 to 3.8 kg. They were anesthetized with intraperitoneal pentobarbitone (30 mg/kg) with later supplementary intravenous doses as required. The animals breathed spontaneously, and at the time of the experiment, arterial blood gases were in the normal range 8'~~of 26 to 34 torr for pCO~ and 85 to 106 torr for pO~. After tracheal and femoral arterial and venous cannulation, a lumbar laminectomy was performed and a cannula passed up alongside the spinal cord intrathecally for several centimeters. It was secured and sealed in by an extradural ligature which included the cord. A parietal burr hole was made and a cannula with multiple punctures at the tip was inserted into the subdural plane and the skull was sealed with dental acrylic. This cannula was attached to a pressure transducer and the output checked for normal pulsations: their presence, and an immediate rise of ICP in response to a small lumbar infusion, allowed repeated confirmation of free communication and patency, and indicated a valid ICP measurement. The following continuous measurements were established on a UV chart recorder (S.E. 2005): pressures from the intracranial cannula (ICP) and from the femoral artery (blood pressure) by photoelectric transducers calibrated in parallel against a mercury manometer; percentage of CO2 in inspiredexpired air from the tracheal cannula, for calculation of end-tidal pCO2 by rapid infrared analyzer calibrated by gas mixtures analyzed on the Lloyd Haldane apparatus; integrated inspired volume (V~) by pneumotachograph with a flow head attached to the tracheal cannula calibrated for flow rates of 2
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to 6 1/min by Rotameter, and being within 5% of linearity at the extremes of this range; instantaneous heart rate (HR), with the BP transducer output used to trigger a Devices ratemeter by an oscilloscope (CRO).* In addition to these continuous records, arterial blood was sampled intermittently, and immediately analyzed for pH, pCO~, and pO2 on the Radiometer system BMS1, calibrated by gas mixtures from a Wosthoff pump.t Measurement temperature was 37 ~ C and the values were corrected to the animal's rectal temperature at the time of each sample, with the Severinghaus blood-gas calculator.$ Mock CSF s~ was used at 37 ~ C for lumbar infusions to raise the ICP; infusion was controlled by hand from a 50-ml syringe, the ICP was raised by 1 mm/sec and then kept constant by watching the display from the ICP transducer on the CRO.
Method for Rising C02
Ventilatory
Response
to
Read's brief rebreathing method ~9 was used, with the technique developed in this
*UV chart recorder (S.E. 2005) manufactured by SE Lab (EMI) Ltd., North Feltham Trading Estate, Feltham, Essex, England. Photoelectric transducers manufactured by Mercury Electronics (Scotland) Ltd., Pollock Castle Estate, Newton Mearns, Glasgow, Scotland. Rapid infrared analyzer (URAS 2000) manufactured by Hartmann and Braun AG, Post Box 900507, Frankfurt, Main, West Germany. Lloyd Haldane apparatus manufactured by Gallenkamp & Co., PO Box 290, Technico House, Christopher Street, London EC2P 2ER, England. Computing Spirometer CS1 manufactured by Mercury Electronics (Scotland) Ltd., Pollock Castle Estate, Newton Mearns, Glasgow, Scotland. Rotameter manufactured by GEC-Elliott Process Instruments Ltd., Rotameter Works, 330, Purley Way, Croydon CR9 RPG, England. Devices ratemeter manufactured by Devices Instruments Ltd., Welwyn Garden City, Herts, England. CRO oscilloscope manufactured by Tektronix Guernsey Ltd., Guernsey, Channel Islands, England. tRadiometer system BMS1 manufactured by Radiometer A/S Emdrupvej, 72 DK 2400, Copenhagen, Denmark. Wosthoff pump manufactured by H. Wosthoff, Buchum, Germany. ~Severinghaus blood-gas calculator manufactured by Radiometer A/S Emdrupvej, 72 DK 2400, Copenhagen, Denmark. ]57
S. Jennett and J. B. North secutive 10 seconds. When these values were plotted in earlier experiments, no consistent relationship other than a linear one was suggested. Subsequently the regression of ventilation on pCOs was calculated by the method of least squares, and when the correlation coefficient was greater than 0.8 the Fx~. 1. Rebreathing apparatus for determination of ventilatory response to rising COs. Animal relationship was accepted as linear; the breathes in and out ofa polythene bag contained in parameters of the regression equation gave a Perspex cylinder. the slope (S) of the response of ventilation to COs and the intercept representing pCOs at zero ventilation (Fig. 2).
Procedure When all recordings were established and baseline blood gases had been measured and found to be acceptably normal, a series of increases in ICP was imposed, each lasting 10 min and each successively 10 mm Hg higher (Fig. 3). Earlier experiments showed that there was rarely any effect on respiration at ICP lower than 50 mm Hg, so this was used as the first pressure. Pressure was always increased at the same rate of 1 mm Hg/sec as smoothly as possible within the limits of manual control. At the end of each 10-min period ICP was allowed to fall, and recovery FIG. 2. Ventilatory response to COs: solid line of the several recorded variables was allowed shows mean slope (S =/xVI/ApCO~) .extrapolated to mean intercept (pCO~ at zero V~) from before the next episode of raised ICP. repeated tests on 10 animals at normal ICP; broken lines indicate the range of slopes found. S Timing of Blood Gas Measurements and was calculated from the linear regression of ven- C02-Response Tests tilation on pCO2 using values for consecutive 10Blood was taken immediately before a second periods during rebreathing. pressure rise, and during the fifth minute at high ICP. To avoid excessive depletion of the blood volume, samples were taken in alternate pressure runs only. The CO2-response laboratory for human subjects, scaled down to appropriate dimensions. The tracheal can- tests were carried out in a similarly paired fashion before and during every high-pressure nula was attached to a polythene bag filled run: the baseline test was between I0 and 5 with approximately 100 ml 5% COs in oxygen, and contained within a Perspex cylinder minutes before the run and the high ICP test was applied just after the arterial blood was sealed except for an attachment to a flow sampled, after 5 to 8 minutes of high ICP head, and sampling and return tubes for COs (Fig. 3). analysis (Fig. 1). Thus, ventilation could be The first 10 cats were used to provide data recorded continuously during the rebreathing for breathing pattern, BP, and blood gas by a bag-in-box method. changes only; in the second 10 cats the venDuring such rebreathing from a gas mixtilatory response to CO2 was also studied. ture with the percentage of COs initially near to the mixed venous pCO2 value, there is a Anesthetic Level brief equilibration period followed by a linear rise in COs and normally a progressive inBy careful reference throughout to the concrease in ventilation. In every test the period tinuous records of end-tidal pCOs, ventilaof this linear rise was defined, and the values tion, and BP, the depth of anesthesia was kept for pCO2 and ventilation found for each con- near constant; supplementary doses were suf158
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Changes with intermittently raised ICP in cats
Fic. 3. Experimental protocol. Each increase of intracranialpressure was maintained for 10 minutes and recovery allowed before the next. All animals were exposedto the levels shown up to 120 mm Hg ICP; some survived to higher levels (broken arrow). Timing of blood gas measurements (arrows) and rebreathing tests (bars) is shown, before and during runs of raised ICP.
ficient only to restore these variables to baseline; paired normal and raised ICP measurements were not started until or unless the animal's state was stable. Results
Ventilation and Pattern o f Breathing In nearly all animals, the first effect observed on the breathing was stimulation. This tended to occur during a rise of pressure; then, as pressure was held constant, hyperventilation might persist, or, at the higher pressures, give way to irregularity, depression, and periods of apnea; there was quite frequently a relative recovery from depression after the first 1 or 2 minutes at pressure; distinct periodicity occurred in less than half the animals. The disturbances became progressively more severe with successively higher pressure levels, until there was apnea with recovery only after release of pressure, and ultimately irreversible apnea. The range of ICP at which these several effects occurred in different animals was very wide: this was partly attributable to variations both in the initial arterial blood pressure and in the extent of the rise in BP when ICP was raised: there was less scatter of threshold values for depression and apnea in terms of cerebral perfusion pressure (CPP, mean B P - mean ICP) (Fig. 4). Persistent apnea occurred at perfusion pressures which still allowed maintained vasomotor activity, as evidenced by the persistence of a raised BP. In one exceptional animal ventilation was consistently stimulated at an ICP of 150 and
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FIG. 4. Threshold ICP values for each effect on ventilation: range (solid lines) and mean (0). Threshold CPP (mean BP - mean ICP) for each effect: range (broken lines) and means (0). The range of threshold values causing ventilatory depression and apnea is smaller for CPP than for ICP. No mean is shown for CPP related to irreversible apnea because at this stage CPP was very variable, due to large swings in BP.
CPP of 27 mm Hg; only at ICP 160 mm Hg was the initial stimulation followed by depression, and apnea occurred at 170 mm Hg. When ventilation was stimulated, there was commonly an increase in both frequency and 159
S. Jennett and J. B. North
FIG. 5. Records showing the several recorded variables during release of raised ICP ( ~ 100 mm Hg) at the end of 10 rain. Starting from the top: Airway percentage of COs (the scale is linear, with the zero offset beyond the UV paper): End-tidal level represents pCO~ of 29 to 30 torr. In this and other experiments, end-tidal and arterial pCO2 values were normally not more than 5 torr different unless tidal volume was exceptionally small. HR = heart rate. BP = arterial (femoral) blood pressure. ICP = intracranial pressure, held within 8 mm Hg of 100; fluctuations followed those of BP. Cumulative inspired volume showed a 30-sec volume of 140 to 150 ml, that is, a ventilation of 280 to 300 ml/min. VT = tidal volume. Note that there had been no significant alteration in minute volume, breathing pattern, or arterial blood gases during this run, although a small change in pattern can be seen after release of pressure. The CPP was 45 to 50 mm Hg: this animal's threshold CPP for ventilatory depression was at the low end of the range shown in Fig. 4. There had been a considerable increase in BP, and a small increase in HR; both are shown returning to baseline. The ICP of 95 to 100 mm Hg, which had been maintained for 10 minutes, was 15 to 20 mm Hg above the animal's baseline diastolic BP.
FIG. 6. Record showing irregularity and depression of ventilation at ICP 100 and CPP ~60 mm Hg. Large falls in BP related to breaths. Traces are as in Fig. 5. PaCO2 = 42 tort and PaO2 = 69 torr during this run (compare with Fig. 8). This animal's threshold CPP for ventilatory depression was at the high end of the range shown in Fig. 4. 160
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C h a n g e s w i t h i n t e r m i t t e n t l y raised I C P in cats tidal volume, but the pattern was not consistent. Depression, however, always entailed a reduction in frequency, with irregularity both of cycle length and of tidal volume. Blood Pressure Changes The arterial BP almost always increased, even with the lowest intracranial pressures applied. The ICP threshold for this response of BP was most often lower than that for the first effect on breathing: in no animal was it higher (Fig. 5). The pressure to which an animal survived was not related to its initial BP; since apnea eventually occurred at perfusion pressures below 30 mm Hg, it follows that the higher the BP response achieved, the higher was the ICP attained before apnea supervened. At the highest ICP levels in each animal, those associated with ventilatory depression and irregularity, BP increased dramatically (in some up to 100% above baseline level), and this was followed by large irregular oscillations as well as a much increased pulse pressure. Ventilation was erratic at this stage, and large gasping breaths were followed immediately by steep reductions in BP (Fig. 6). These latter observations at high pressures were consistent with many earlier investigations; however, the increases in BP at lower ICP's differ from the findings of some authors, such as Weinstein, et al? 4 Results are presented and discussed in detail elsewhere. 15 Heart Rate Changes
Ventilatory Response to Rising C02 Variation in the parameters of the response was considerable, not only between animals, but also in any one animal. Because of variations associated with minor fluctuations in anesthetic level and body temperature, values were compared before and during each individual high-pressure run and each change expressed as a percentage. Even so, separation by about 15 minutes could account for considerable random differences in the slope of the CO2-response line (S). In two animals studied as controls, without increases in ICP, the variation in S was similar to the variation between responses at normal ICP in the experimental animals. Examples of paired values for three experimental animals and one control animal are shown in Fig. 7. No change was consistently attributable to raised ICP until or unless there was clear interference with breathing pattern and ventilatory depression breathing air. In most animals there were two or three penultimate levels of high ICP at which the response to COs was lost, and at which there was gross irregularity of breathing, yet from which recovery was complete within 3 to 5 minutes of release of pressure after the 10-minute exposure. The values for intercept were treated similarly to those for slope, and did not show any consistent effect attributable to pressure in advance of ventilatory depression. Intercept was a less variable value than slope. There was no tendency for this value to increase with raised ICP.
The earlier, less dramatic, increases of BP Arterial Blood Gases were usually accompanied by small increases in HR. Only the later steep increases were Paired values before and during high ICP associated with decreasing HR (Fig. 6). Large runs showed no changes other than those swings of heart rate sometimes accompanied related to varying anesthetic level, until venthe infrequent very deep gasping breaths of tilatory depression occurred: there were small severe respiratory depression. As in normal changes in PaCO~ accompanied by changes in sinus arrhythmia, an increase in H R began PaO2 in the opposite direction, and of an apwithin 1 second of the start of inspiration; in propriate extent. The predicted PaO2-PaCO2 one animal only, we saw an increase in the relationship for cats under pentobarbitone amplitude of respiratory sinus arrhythmia anesthesia was defined by pooling data from which was not attributable either to a reduc- 28 animals breathing air, at normal ICP, tion in mean heart rate or to an alteration in from this and an earlier series. Points were breathing pattern. We could not confirm in plotted on a pO2-pCO2 diagram 28 (Fig. 8). this series the suggestion that there may be a The overall mean values at normal ICP consistent specific effect of raised ICP on the were PaO2 97.9 torr and PaCO2 30.3 torr. amplitude and the time-course of sinus The mean PaO2 for all raised ICP runs was arrhythmiag ,8 91.6 torr and PaCO2 33.7 torr; for this J. Neurosurg. / Volume 44 / February, 1976
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F~. 7. Pairs of values for the ventilatory response to rising CO2 during rebreathing. Each slope represents the linear regression line calculated from data for ventilation and pCO2 in the manner described in the text, and Fig. 2. A slope of 45 ~ is equivalent to an increase of 100 ml/min/unit increase in pCO2. The top three sets are from three of the experimental animals. The solid lines show the consecutive values for S measured at normal ICP, before each experimental increase in ICP. The broken lines show the values for S during raised ICP, at the levels shown beneath each pair of slopes. The pairs of estimations before and during the smaller increases in ICP show a random difference attributable to the error of the method and small variations in depth of anesthesia; X at the highest ICP levels indicates that there was not any significant response to CO2: ventilatory depression breathing air was already evident at these pressures and at the one or two penultimate levels at which S was diminished. The lowest set of values is from a cat studied over a comparable period with similar anesthesia. In all these animals, S changed inversely with end-tidal pCO2, whether the variation in the latter was related to minor variations in depth of anesthesia, or to ventilatory depression at high ICP.
minimal degree of hypoxemia to be attributable to hypoventilation, PaO2 should be similar to the value at the coexisting PaCO2 predicted from the relationship defined at normal ICP: the predicted value is 91.7 torr. Four animals appeared to show a disproportionate hypoxemia at their highest ICP; however, similar reduction in PaO2 could be brought about at normal I C P when ventilation was depressed by increments of pentobarbitone (Fig. 8). "162
Discussion
Method o f Increasing ICP We chose a hydrostatic method in order to avoid the complicating effects of brain shift and herniation, and of supra- and infratentorial pressure differences; an earlier unpublished series of experiments in eight cats had indicated that raising I C P by subdural balloon inflation led to very inconsistent
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Changes with intermittently raised ICP in cats effects on breathing, and entailed difficulties in maintaining steady pressures and in measuring confidently the relevant ICP; some animals failed to recover completely from 10 minutes at relatively low pressures by the balloon method, while lumbar infusion could be applied repeatedly and to quite high levels in many animals, with complete recovery between runs. Many reported series have employed prolonged, progressively rising or stepwise increases in ICP. We chose intermittent increases lasting only 10 minutes and compared the several measurements with values found FIc. 8. Black circles indicate data from 28 immediately preceding that pressure rise; thus, any effect would have been seen which animals at normal ICP breathing air under pentobarbitone anesthesia; solid line is the regression was a direct or reflex result of that pressure, line. Broken line is the comparable regression line rather than its more indirect, delayed, or for values (not shown) for all cats at all levels of cumulative effect. Also, waves of increased raised ICP. Open circles are values during the pressure are common clinically, and often of most severe ventilatory depression during raised ICP, from each of 11 cats. Crosses show values comparable duration, so this model may from each of two cats when ventilation was more nearly imitate real conditions than the depressed by increments of pentobarbitone. imposition of continually rising or maintained pressure. The rate of rise of pressure was kept constant for all animals and all ICP levels so that differing effects due to varying rates of rise at the highest levels. Such rises in BP necessarily entail a large increase in symwere excluded. pathetic outflow." This is relevant when one considers the possibility of any sympathetic Perfusion Pressures effect on the pulmonary vascular bed. We are Many investigators have chosen to apply a satisfied that we were studying in these exconstant level of ICP, or to impose a level periments a condition in which there was inrelated to each animal's initial arterial BP. deed an increase in sympathetic activity. We have confirmed the numerous obserOur experience emphasized that any one level of ICP was far from comparable from one vations that when ICP rises, respiratory animal to another, because of variation in ini- center activity ceases before vasomotor actial BP and in the animals' BP response. To tivity; however, it is possible that the compare animals we estimated the perfusion vasomotor response might have been mainpressure, calculated conventionally as mean tained in part by the effect on spinal centers arterial BP minus mean ICP. However, this of raised pressure, la,3~ does not make experiments comparable in terms of medullary blood flow, since the state Response to Rising C02 of cerebral vasodilatation at any one perfuThe ventilatory response to COs did not sion pressure varies between animals. usually show any significant change in any We have shown that severe ventilatory one animal until ventilatory depression was depression generally occurs at a CPP below already evident. 40 to 60 mm Hg, which is regarded as the There was a suggestion that the response level below which CBF is no longer unwas diminished at a slightly lower ICP than changed by vasodilation. 19'a5 the level causing ventilatory disturbance, but it was not significant enough to suggest a Sympathetic Activity useful application in detecting imminent venThe magnitude of the BP response was tilatory disturbance clinically. The interpretacommonly progressive with increasing ICP tion of the effects of COs breathing is comand was always considerable (30% or more) plex since it provokes not only a ventilatory
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"163
S. Jennett and J. B. North but also a cerebrovascular response which further increases the ICP when it is not deliberately kept constant as in these experiments. Our results of such tests in patients are reported elsewhere. 23 The decline in response to CO2 pari passu with the development of hypoventilation on air, would be consistent with depression either of respiratory neurons themselves, or of central chemoreceptors.
Breathing Pattern The stimulation of breathing during pressure rise seems to occur in some patients during spontaneous increases of ICP. 24 It could be a direct and specific effect of pressure, but if so, would be unlikely to pass off after the initial rise, as it did in many animals; a stimulation of breathing has been noted during localized pressure on the brain stem. ~s Alternatively, an initial reduction in blood flow, with increase in acidity around the medullary chemoreceptors, might be returned to normal as local vasodilatation occurs. Chemical effects of the infused fluid on the surface of the spinal cord or medulla are unlikely to have accounted for the ventilatory changes, because of the absence of such effect during infusion at pressures lower than each animal's "threshold" ICP. We rarely saw persistent hyperventilation at high ICP, as that reported in approximately 50% of rabbits '7 and in all cats after cold lesions. ~ In these latter experiments, it was reported that a phase of periodicity was followed by rapid respiration, a sequence which we never saw. The example of tachypnea shown consists of regular breathing at a frequency of 25/min, which is about normal, in our experience, for anesthetized cats (Fig. 5). The absence of blood gas values also makes it difficult to know whether there was a true hyperventilation. Increased ventilation at high ICP has also been reported in dogs ~ but the situation was complicated by hypoxemia. The depression of ventilation which occurred with diminishing perfusion pressure was consistent with a great many observations by others. This disturbance has usually been attributed to local hypoxia due to brain-stem ischemia. In models in which pressure is raised asymetrically and supratentorially, distortion might readily account
16d
for such an effect; in hydrostatically raised pressure, with evidence of free communication between compartments, this factor would appear to be excluded. The direct, symmetrical effect of pressure or some indirect effect on the respiratory center must be held to account. Ventilation was often partly inhibited at perfusion pressures in the range of 40 to 60 mm Hg; such perfusion pressures during raised ICP (in other species) are reaching the point at which cerebral vasodilatation fails to maintain blood flow at its normal value. 19,3s Therefore, CPP in this range is unlikely to be associated with less than 70% to 80% of normal blood flow. Since ventilatory depression by systemic hypoxia does not occur until the PaO2 falls as low as 20 to 30 torr, it seems unlikely that the reduced oxygen delivery in an undistorted brain stem, during our conditions of raised ICP, would cause a sufficient decrease in tissue pO2 to depress the breathing. But the local capillary blood flow might be peculiarly vulnerable. Perhaps a failure of stimulation, or an inhibitory influence on the respiratory neurons from another site should be considered.
Arterial Blood Gases Such hypoxemia as we found in these experiments appears to be explicable without invoking any effect of ICP on the lungs themselves. We have explained the reasons for regarding the PaO~ values as related simply to the central depression of breathing, with hypoventilation and hypercapnia. Other investigators have reported hypoxemia without raised PaCO2 at high ICP, notably in dogs: either a reduction in PaO2 breathing oxygen2 or an actual hypoxemia breathing air. 21 The initial arterial pO2 values were below normal in both series, which suggests a significant pre-existing shunt or ~la/O imbalance, against which background the raised ICP effect is difficult to assess. The discrepancies might represent a species difference. However, other experiments on dogs have not shown hypoxemia. 25 It might be suggested that the difference is one of duration. If we had maintained high ICP for longer, hypoxemia might have developed: Berman and Ducker 2 report a "progressive" hypoxemia. However, if the effect is attributable to sympathetic activity, we would expect to see it at the height of such activity, at high pressures which invoke a large BP
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Changes with intermittently raised ICP in cats response. At such pressures, the hypoxemia in our cats was again only equivalent to the extent of ventilatory depression. From our experience in these studies we have become aware of certain criteria which must be fulfilled before hypoxemia can be attributed to an effect of high ICP on the lungs. Attention must be paid to correction of pO2 values for body temperature which may be difficult to control; the predicted decrease in pO2 for a given increase in pCO2 for the particular species and anesthetic must be known, so that changes related to hypoventilation can be properly assessed; the arterial blood gases must be normal in the baseline conditions because otherwise hemodynamic changes associated with raised ICP may, on the background of existing abnormality, cause alterations in venous admixture which could be confused with a primary effect of pressure; the arterial blood gases should return to normal once the pressure is released. Within these criteria, we have been unable to demonstrate a hypoxemic effect. Clearly there are many other ways in which acute brain damage in general, and raised ICP in particular, can be associated with arterial hypoxemia, is One such situation is the occurrence of pulmonary hemorrhage and edema, from which the proposed mechanism for production of hypoxemia is to be distinguished. 2 In our view the evidence for a neurally mediated effect on the lungs causing hypoxemia is not yet convincing, and the further step to treatment by sympathetic blocking agents 3,2~ could interfere with compensatory mechanisms.
Effect o f Anesthesia The results from this series of cats under pentobarbitone anesthesia may not be applicable to other species, other anesthetic agents, or to awake animals or man. Some differences from other series may be related also to the depth of anesthesia. The low threshold for BP response and the occurrence of stimulation of ventilation may have been because our animals were kept at a level which maintained a near-physiological pCO~ (around 30 torr), rather than the somewhat higher values often reported. Within the series, and within each animal, care was taken to distinguish the effects of changing depth of anesthesia from those of raised ICP.
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Conclusion
We have demonstrated that, in anesthetized cats, when ventilation is depressed by raised intracranial pressure, the alterations in blood gases and in ventilatory responsiveness to increasing CO2 are related to the extent of the hypoventilation; the changes are similar to those which occur with increasing depth of anesthesia. There is, thus, no need to postulate a specific effect of increased ICP on pulmonary gas exchange. Acknowledgments
We acknowledge the benefit of suggestions and discussion by Drs. J. T. Hoff and J. D. Miller, and of technical assistance by G. Burnside and Alexis Young. References
1. Beks JWF: Effects of increased supratentorial pressure in cats. J Neurol Neurosurg Psychiatry 37:627-630, 1974 2. Berman IR, Ducker TB: Pulmonary, somatic and splanchnic circulatory responses to increased intracranial pressure. Ann Surg 169:210-216, 1969 3. Brackett CE: Respiratory complications of head injury, in International Symposium on Head Injuries. Edinburgh, Churchill Livingstone, 1971 (US distributors: Williams & Wilkins), pp 255-265 4. Briggs M, Adams AP" Ventilatory and intracranial pressure responses to CO2 stimulation. Br J Surg 60:315, 1973 5. Cushing H: Some experimental and clinical observations concerning states of increased intracranial tension. Am J Med Sci 124: 375-400, 1902 6. Dejours P, Lacaisse A: Arterial blood pH and partial pressures of O5 and CO2 in normal awake cats. J Physiol (Paris) 63:87-90, 1971 7. Fitch W, McDowall DG: Vasodilating anaesthetics and pressures in different compartments of the skull, in Brierley JB, Meldrum BS (eds): Brain Hypoxia. Philadelphia, London, W Heinemann Medical Books, 1971 (US distributor, JB Lippincott), pp l l3-117 8. Heck AF: Cardiorespiratory interaction during increased intracranial pressure, in Brock M, Dietz H (eds): Intracranial Pressure. New York/Heidelberg/Berlin, Springer-Verlag, 1972, pp 200-204 9. Heck AF: Cardiovascular and respiratory changes during transient increase in intracranial pressure, in Feischi C (ed): Cerebral Blood Flow and Intracranial Pressure. Basel, S
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23. North JB, Jennett S: Cerebrovascular response pattern during rebreathing, in Langfitt TW, McHenry LC Jr, Reivich M, et al: Cerebral Circulation and Metabolism. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 249-250 24. North JB, Jennett S: The interpretation of simultaneous recordings in patients of breathing pattern and intracranial pressure, in Lundberg N, Pont6n U, Brock M: lntracranial Pressure II. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 460-463 25. Pitts LH, Severinghaus JW, Mitchell RA, et al: The role of increased intracranial pressure in the production of neurogenic pulmonary edema, in Lundberg N, Pont6n U, Brock M: lntracranial Pressure II. New York/Heidelberg/Berlin, Springer-Verlag, 1975, pp 319-323 26. Plum F, Brown HW: The effect of respiration on central nervous system disease. Ann NY Acad Sci 109:915-931, 1963 27. Plum F, Brown HW: Hypoxic-hypercapnic interaction in subjects with bilateral cerebral dysfunction. J Appl Physiol 18:1139-1145, 1963 28. Rahn H, Fenn WO: A graphical analysis of the respiratory gas exchange: the O2-CO2 diagram. Washington DC, American Physiological Society, 1955 29. Read DJC: A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Meal 16:20-32, 1967 30. Rowan JO, Johnston IH: Blood pressure response to raised CSF pressure, in Lundberg N, Pont~n U, Brock M: Intracranial Pressure II. New York/Heidelberg/Berlin, SpringerVerlag, 1975, pp 298-302 31. Schlaefke ME, See WR, Loeschke HH: Ventilatory response to alterations of H § ion concentration in small areas of the ventral medullary surface. Respir Physiol 10:198-212, 1970 32. Staunton C, Stein AA, Moss G: Cerebral etiology of the respiratory distress syndrome: universal response, with prevention by universal pulmonary denervation. Surg Forum 24:229-231, 1973 33. Szidon JP, Fishman AP: Autonomic control of the pulmonary circulation, in Fishman AP, Hecht HH (eds): Pulmonary Circulation and Interstitial Space. Chicago, University of Chicago Press, 1969, pp 239-268 34. Weinstein JD, Langfitt TW, Kassell NF: Vasopressor response to increased intracranial pressure. Neurology (Minneap) 14:1118-1131, 1964 35. Zwetnow NN: Cerebral blood flow autoregulation to blood pressure and intracranial
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Changes with intermittently raised ICP in eats pressure variations. Seand J Clin Lab Invest Suppl 102:V-A, 1968
This work was supported in part by a grant to Dr. Jennett from the Scottish Hospital Endowments Research Trust.
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Dr. North was the recipient of a Commonwealth Medical Fellowship. Present address for Dr. North: Neurosurgical Clinic, Royal Adelaide Hospital, Adelaide, South Australia. Address reprint requests to: Sheila Jennett, M.D., Ph.D., Institute of Physiology, Glasgow G12 8QQ, Scotland.
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