(Stroke. 1997;28:141-148.)
© 1997 American Heart Association, Inc.
Articles |
Ventricular Dilatation in Experimental Intraventricular Hemorrhage in Pigs
Characterization of Cerebrospinal Fluid Dynamics and the Effects of Fibrinolytic Treatment
the Departments of Neurosurgery (L.M., J.K., R.R., P.D., J.M.G.), Neuropathology (J.W.), and Neuroradiology (W.K.), Medical Faculty of the University of Technology (RWTH), Aachen, Germany.
Correspondence to Lothar Mayfrank, MD, Department of Neurosurgery, Medical Faculty of the RWTH, Pauwelsstrasse 30, D-52057 Aachen, Germany.
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Background and Purpose Hemorrhagic ventricular dilatation (HVD) is a prominent feature of human intraventricular hemorrhage (IVH) and a strong indicator for poor outcome. We developed an IVH model to define the mechanisms responsible for HVD and to test the efficacy of intraventricular administration of tissue plasminogen activator (TPA) in the treatment of HVD.
Methods Isolated IVH was produced in pigs by injecting 10 mL of blood simultaneously with thrombin into the right lateral ventricle. The treatment group received 1.5 mg of TPA after induction of IVH. Intraventricular blood volume and the volume of the lateral ventricles were assessed by CT after 90 minutes, 7 days, and 42 days. Intracranial pressure, the pressure-volume index, and the resistance to outflow of cerebrospinal fluid (Rout) were measured 30 minutes and 7 days after IVH.
Results After IVH, the volume of the lateral ventricles increased from 1.98±0.69 to 6.43±1.23 mL (P<.001). There was a linear relationship between ventricular and clot volume (P=.014). Initially, Rout increased from 24.34±7.13 to 63.56±64.91 mm Hg/mL per minute (P<.001). After 7 days, restoration of normal cerebrospinal fluid circulation occurred, but the ventricles were still significantly enlarged (5.24±1.76 mL, P<.001) and filled with blood. Within 6 weeks, ventricular volume had returned to normal values, paralleled by complete clot resolution. Intraventricular administration of TPA significantly accelerated clot clearance and restoration of normal ventricle volume.
Conclusions These results suggest that intraventricular bleeding may cause impairment of cerebrospinal fluid circulation but that the mass effect of clots distending the ventricle walls is the most important mechanism responsible for HVD. This model closely imitates several prominent features of human IVH and may therefore be a useful tool for preclinical assessment of the efficacy and safety of treatment with TPA.
Key Words: cerebral hemorrhage • hydrocephalus • intraventricular hemorrhage • plasminogen activator, tissue-type • pigs
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Primary IVH, ie, bleeding confined to the ventricular system, is rare in adults.1 2 However, IVH is a frequent complication of ICH and aneurysmal SAH. It is well known that intraventricular bleeding is associated with high mortality and a poor functional outcome.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Moreover, in patients with ICH, intraventricular spread of the hemorrhage has been shown to be one of the most powerful independent predictors for mortality and permanent disability.3 5 8 13 16 23
Until now, the mechanisms by which intraventricular blood causes brain damage have been poorly understood. Dilatation of the ventricles is a characteristic feature of severe IVH and has been reported to have a strong negative impact on the patients' survival and neurological outcome. Mohr et al14 reviewed patients with IVH secondary to aneurysmal SAH and found that the degree of HVD was closely correlated with mortality. Shapiro et al19 analyzed 50 patients with IVH of various causes and showed that HVD of the fourth ventricle was the most important predictor of the eventual outcome. However, neither the pathophysiological basis of HVD nor its therapeutic implications have been clarified. According to some authors, HVD is primarily induced by impaired CSF circulation due to obstruction of CSF outflow pathways.10 14 Consequently, many clinicians attempt to treat IVH-related ventriculomegaly by ventricular drainage, which is thought to lower CSF pressure.7 10 14 However, the changes in the dynamics of the CSF system induced by intraventricular blood have never been investigated experimentally or clinically. According to Shapiro et al,19 the major factor responsible for the induction of HVD and its accompanying poor prognosis is the mass effect of clots distending the ventricle walls, independent of the obstruction of CSF pathways. If this is the case, CSF diversion alone would be of little help, and strategies designed to remove intraventricular clots to decrease compression of the periventricular neural and vascular structures should be developed. Investigations into the mechanisms involved in HVD are particularly interesting in the light of recent reports suggesting that marked acceleration of intraventricular blood clearance can be achieved by recombinant TPA administered into the ventricles.25 26 27 28
To elucidate the mechanisms leading to brain damage from IVH, we have developed an animal model of IVH in pigs. The present studies were performed to define the mechanisms responsible for HVD and to test the efficacy of TPA in the treatment of HVD after experimental IVH. To the best of our knowledge, this is the first published experimental study that characterizes CSF flow dynamics associated with IVH and that investigates the effects of TPA in experimental IVH.
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The experimental protocols were in conformity with the Federal Law for the Protection of Animals and were reviewed and approved by the local authorities.
Animals
Thirty-two male pigs (German Land Race) weighing 24 to 34 kg were used in this open study. They were divided into (1) a nontreatment group of 18 animals that underwent intraventricular blood injection without further treatment and (2) a treatment group of 14 animals. In the latter group, TPA was administered into the ventricles after the injection of blood. In each group, half of the animals were assigned to a follow-up of 7 days and 42 days, respectively.
Animal Preparation
The pigs were premedicated with 500 mg ketamine, 1.0 mg atropine, and 160 mg azaperone IM. Anesthesia was induced by injection of 60 mg pentobarbital IV and maintained with continuous infusion (120 mg/h), supplemented by bolus injections as required. The animals were intubated and ventilated with a conventional respirator with a 5:3 mixture of nitrous oxide and oxygen. Ventilation was adjusted to maintain arterial CO2 between 32 and 38 mm Hg. A catheter was placed into the left common carotid artery for continuous monitoring of blood pressure, blood gas analyses, and withdrawal of blood for intraventricular injection. Body temperature was maintained within normal limits with a heating blanket.
The pigs were placed in a stereotaxic head holder in the sphinx position. The head was fixed such that the external auditory meati and the ventral lacrimal foraminae were at the same horizontal plane,29 30 with the external auditory meati positioned at the level of the heart. A midline scalp incision was performed and a burr hole placed in front of the coronal suture and on the right hand side. An 18-gauge cannula was placed stereotaxically into the right lateral ventricle; this cannula was used to record CSF pressure and inject blood into the ventricles (see below for details). The cannula was inserted perpendicularly 10 mm anterior to the bregma, 4 mm lateral to the midline, and 20 mm below the dura. The cannula was connected to a pressure transducer, positioned at the level of the external auditory meati, and then slowly drawn back until typical CSF pressure waveform amplitudes had reached a maximum. Intraventricular placement of the needle tip was confirmed by typical pressure responses to test injections of 0.1 to 0.5 mL of saline and by CT of the intraventricular location of injected blood. As determined by this technique, the final position of the needle tip was located at a depth ranging between 15 and 17 mm measured from the dura mater. The burr hole around the needle was closed with bone wax.
A volume of 10 mL of blood was obtained from the carotid artery catheter and immediately reinjected into the ventricle along with 140 U thrombin (Thrombocoll, Johnson & Johnson Medical) dissolved in 0.7 mL normal saline. A simultaneous injection of blood and thrombin was performed through a three-way stopcock connected to the ventricular cannula over a period of 2 minutes. The system was then flushed with 0.5 mL saline to prevent obstruction of the cannula.
Commencing 30 minutes after IVH, animals in the treatment group received three doses of 0.5 mg TPA (Actilyse, Thomae) dissolved in 0.5 mL saline (following the manufacturer's suggestion), delivered at a rate of 0.1 mL/s through the ventricular cannula. The interval between one injection and the next was 5 minutes. Thus, each animal received 1.5 mg TPA in a volume of 1.5 mL. The animals of the nontreatment group received the same volume of saline instead of TPA.
Ninety minutes after the injection of blood, the pigs underwent CT scanning of the brain in the coronal plane. Anesthetics were then discontinued, and the animals were allowed to recover. At survival times of 7 or 42 days, all surviving pigs were reanesthetized, and a CT scan of the brain was performed. Additionally, in the 7-day follow-up group the right lateral ventricle was cannulated stereotaxically, and CSF pressure parameters were measured. At the end of this procedure, pigs were killed by injection of potassium chloride, and the intact brains were removed from the cranium and fixed in 4% paraformaldehyde before being sectioned.
Posthemorrhage Evaluation
The clinical status was checked daily, and any abnormalities concerning level of consciousness, behavior, and neurological status were recorded. An animal was considered to be in an acceptable clinical condition if it was alert and able to stand on all four legs and eat and drink without assistance. Any animal that did not meet these criteria for more than 6 hours a day was killed.
In all animals, intraventricular CSF pressure was continuously recorded before the intraventricular injection of blood and for the subsequent 20 to 40 minutes. Neural axis volume buffering capacity and CSF outflow resistance were assessed in all animals before the injection of blood and again after 7 days in all 12 animals that survived until the end of that follow-up period.
Neural axis volume buffering capacity was measured with the PVI technique of bolus manipulation of CSF.31 32 33 34 35 After an initial steady state ICP (P0) was established, repeated bolus injections of 0.5 to 1.0 mL saline were performed at a rate of 0.1 mL/s. The PVI was calculated according to the formula of Marmarou et al31 32 :
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V is the injected volume, Pmax the peak ICP immediately after bolus injection, and Pmin the ICP before bolus injection.
The resistance to outflow of CSF (Rout) was determined with the use of the bolus technique as described previously, according to the following equation31 32 :
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In 11 randomly selected animals, CSF pressure was monitored during bolus injections of saline, performed 30 minutes after the induction of IVH (see previous section), and PVI and Rout were calculated to assess early changes of the volume buffering capacity and of resistance to outflow. The CSF pressure recorded 30 minutes after IVH, before bolus injection, was taken as P0 (to calculate Rout according to the above equation). As a result of the fact that 30 minutes after IVH, CSF pressure was still falling and had not reached its new steady state level (Fig 1
), the calculation resulted in a systematic underestimation of Rout.
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The volumes of the lateral ventricles and of the clot within the lateral ventricles were measured on the CT scans obtained 1.5 hours after IVH (n=29) and after 7 and 42 days in the 23 animals that survived until the end of the follow-up periods. To obtain normal values for the volume of the lateral ventricles, CT scans of nine animals, randomly selected from the entire group, were performed before the initial operation. Volumetric analysis was performed with a microcomputer-based technique described and validated previously.36 37 38 In brief, the films were placed on a translucent digitizing tablet (AccuGrid, Numonics) interfaced to a microcomputer running PC3D software (SigmaScan/Image, Jandel Scientific), a three-dimensional reconstruction program. The perimeters of the lateral ventricles and of the clots were traced and the cross-sectional areas calculated. The areas of contiguous slices were added and multiplied by the slice thickness (4 mm in our study). Volumetric analyses were performed by two of the authors, who were not informed regarding results of ICP measurements, treatment, outcome, and length of the interval between blood injection and CT scanning.
The amount of residual blood within the ventricles at the end of the experiment was assessed by autopsy. The fixed brains were cut in coronal slices of 5-mm thickness, and the blood present in the lateral, third, and fourth ventricles was graded according to a numerical system explained in Table 1.
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Statistical Analysis
All data are presented as mean±SD. Variables were compared between groups with the Wilcoxon test (two-tailed). Correlations between intraventricular clot volumes and the volumes of the lateral ventricles were performed by means of linear regression, and the correlation coefficient r was established. A value of P<.05 was considered statistically significant.
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Inadvertent injection of blood into the frontal lobe, revealed by CT, occurred in three pigs. All data obtained from these animals (including all measurements of ICP) were excluded from analysis. Five animals did not recover from surgery. They presented a severely depressed level of consciousness and died within 36 hours. One animal was killed 4 days after IVH because it failed to meet the acceptable clinical status (as defined previously). Thus, 23 pigs (12 in the nontreatment group and 11 in the treatment group) survived until the end of the follow-up period. Two pigs were slightly ataxic; the remaining 21 had no apparent neurological deficit.
ICP and CSF Dynamics
Baseline ICP was 4.40±1.65 mm Hg. During the injection of blood, ICP increased considerably up to 130 mm Hg. One minute after the injection of blood, ICP had fallen to 61.4±12.3 mm Hg. This was the shortest time interval in which reliable ICP measurements could be performed in all animals. Thereafter, ICP fell, showing a broad spectrum of interindividual rates (Fig 1
). Thirty minutes after IVH, ICP was still significantly higher than baseline ICP (P<.001).
Results from measurements of ICP, PVI, and Rout performed before IVH and at 30 minutes and 7 days after IVH are summarized in Table 2. Thirty minutes after IVH, the PVI was significantly lower (P<.001) and Rout (underestimated for the reasons described previously) was significantly higher (P<.001) than before the injection of blood. Seven days after intraventricular injection of blood, ICP in control, non–TPA-treated animals was slightly but significantly elevated compared with baseline values (P<.05) but was not statistically different from baseline values in the animals that received TPA. The PVI was slightly higher than the baseline values in both the treatment and nontreatment groups (both P<.05). Rout was no longer elevated in the treatment or nontreatment groups.
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Ventricular and Clot Volumes
The lateral ventricles were incompletely filled with blood and considerably enlarged 1.5 hours after simultaneous intraventricular injection of blood and thrombin, as demonstrated by CT. A representative example is shown in Fig 2. The volume of the lateral ventricles increased from 1.98±0.69 to 6.43±1.23 mL in the animals that were not treated with TPA (n=15; P<.001). There was a significant correlation between the volume of the lateral ventricles and the volume of the clot in both the nontreatment and treatment groups (Fig 3). The volume of the clot was lower in the TPA-treated animals (3.38±0.95 mL; n=11) than in the nontreated animals (4.70±0.69 mL; n=15; P<.001). Ventricular volume was also significantly lower in the treatment group as early as 1.5 hours after IVH (4.78±1.09 mL; P<.001) (Fig 4). Seven days later, ventricular size had almost returned to normal values in the animals treated with TPA (n=6), while it was still considerably enlarged in the nontreatment group (5.24±1.76 mL; n=6; P<.001). At that time, the central core of the blood clot could still be differentiated on CT scans in the nontreatment group. However, it became difficult to identify the borders of clots, since the density of the periphery had decreased markedly to values near that of the periventricular brain tissue, thus preventing reliable volume measurements to be made based on image analysis. No blood was visible on CT scans in the treatment group. Within 42 days, ventricular volumes had returned to the mean baseline value in both the treatment (n=5) and the nontreatment (n=6) groups.
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Coronal brain sections performed at the end of follow-up revealed large amounts of blood in the nontreatment group 7 days after IVH. The IVH score (according to Table 1) was 5.50±1.76; in contrast, no residual blood was present in any of the TPA-treated animals. This difference was statistically significant (P<.01). After 42 days, no residual clots were visible in either group.
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Methodological Considerations
Thus far, most experimental studies dealing with cerebral hemorrhages have focused on the effects of intraparenchymal blood on the adjacent brain tissue. In the present study we examined the specific pathophysiological consequences of bleeding within the ventricular system. We therefore developed an experimental model of "pure" IVH.
Experimental investigation of the effects of IVH on CSF flow dynamics and on ventricular volume requires a model with several essential characteristics: (1) The amount of ventricular blood must be large enough to induce significant ventricular dilatation; (2) the blood should remain within the ventricles for prolonged periods of time, because slow elimination of blood with clots persisting for up to several weeks is a feature typical of adult human IVH12 39 40 ; (3) the hematoma must be confined to the ventricular system, because subarachnoid spread of the hemorrhage could induce ventricular dilatation and impaired CSF circulation capable of overshadowing the effects of IVH17 41 42 43 ; and (4) repeated in vivo neuroradiological examination to assess initial clot volume and the dynamics of ventricular dilatation should be possible.
To the best of our knowledge, the only published model that fulfills these requirements is that described by Pang et al,44 45 46 which produces large ventricular hematomas and considerably enlarged ventricles in adult dogs. To fill the ventricles, Pang et al injected preclotted blood that had been prepared outside the body, because the injection of fresh, unclotted, autologous blood did not produce a solid blood cast in the ventricular system.44 In preliminary experiments with pigs we had the same experience, in that only small amounts of blood remained within the ventricles, with most of it washed out into the basal cisterns, as demonstrated by autopsy (L. Mayfrank, R. Raoofi, unpublished data, 1995). The most likely explanation for the rapid washout of blood is that the concentration of coagulation factors is extremely low in normal CSF. It is interesting to speculate whether acceleration of intraventricular clotting occurs in the case of parenchymal hematomas spreading into the ventricles as a result of exposure of coagulation factors of the cerebral tissue to the CSF.
To accelerate coagulation, we simultaneously injected blood and thrombin into the ventricles, thus preventing the blood from spreading into the basal cisterns. As shown here, this technique reliably produces large intraventricular clots and considerably enlarged ventricles, while only small amounts of blood, if any, are found in the basal cisterns at autopsy.
It is well known that the lysibility of a blood clot depends on its composition and structure.47 48 49 Therefore, one might argue that thrombin, added to accelerate intraventricular coagulation, might interfere with the action of plasminogen activators that we intended to use later in the experiments. In fact, the results of previous in vitro experiments showed that the addition of thrombin to whole blood results in clots that are more resistant to TPA-induced fibrinolysis and that higher TPA doses may be necessary to achieve comparable degrees of lysis.50 We do not believe, however, that this compromises our results, because the present study was not designed to assess the dose-action relationship of TPA after intraventricular administration.
There are no previous studies on the use of TPA for lysing hematomas within the CSF in pigs; furthermore, TPA had never been administered into the ventricles after experimental IVH in any animal species. Thus, the dose of TPA needed for clot lysis in the present model was not known when these experiments were started. Indications for the dose required to dissolve the clots may be derived from studies that had investigated the effects of TPA after experimental SAH51 52 and after IVH in patients.25 26 27 28 However, these data might not be applicable to the situation in pigs because it is well known that the susceptibility of clots to lysis by TPA varies significantly between different animal species.48 We decided to inject 1.5 mg TPA in analogy to the study of Findlay et al.51 These authors had shown that this dose was effective in lysing subarachnoid blood clots in a model of SAH in primates. The mean clot volume of 4.38 mL was similar to the intraventricular clot volume in our study. After it was shown that 1.5 mg TPA significantly accelerated the lysis of intraventricular clots, no efforts were undertaken to further investigate the dose-effect relationship.
Ventriculomegaly and CSF Dynamics After IVH
Ventricular dilatation is a frequent radiological finding in severe human IVH and a strong indicator for poor prognosis.10 14 19 Little attention has been given to the changes in CSF flow dynamics. Mohr et al14 ascribed ventricular dilatation to obstruction of the ventricular outflow pathways of CSF. However, ICP was not mentioned, and CSF outflow was not assessed in their study. Kosteljanetz53 found Rout to be increased in a series of 17 patients with IVH, but since the underlying cause was SAH in all but two cases, the role of IVH could not be isolated from his data.
The present study shows that large amounts of intraventricular blood may cause an acute impairment of CSF circulation, as demonstrated by significantly elevated Rout 30 minutes after induction of IVH. The most likely explanation is that ventricular CSF outflow pathways are obstructed by solid blood clots. As a consequence of pathologically elevated Rout, additional volumes of CSF will accumulate, and ICP will increase. In this circumstance, the degree of ICP elevation partly depends on the volume buffering capacity of the neural axis, which can be reliably assessed by the PVI technique.31 32 33 34 35 The volume buffering reserve proved to be significantly decreased by the blood injected into the cerebral ventricles. Both mechanisms—the compromised CSF circulation and the reduced PVI—will act synergistically and cause an elevation of ICP after the induction of IVH. It seems likely that the degree to which PVI and Rout were altered could account for the variability of the decrease in ICP noted after the induction of IVH, but we have no further data to confirm or disprove this notion.
To some extent, the early increase in Rout might have contributed to ventricular dilatation in the acute stage of IVH. However, our results clearly indicate that impaired CSF circulation is not the major factor accounting for the degree of ventriculomegaly, especially at later stages. One week after IVH, the ventricles of the untreated animals were still considerably enlarged and contained significant amounts of blood, while Rout had returned to normal baseline values. This suggests that ventricular dilatation was mainly caused by the mass effect of the clots distending the ventricular walls. This notion is further supported by the linear relationship between the volume of the clot and the degree of ventricular enlargement, as demonstrated by the initial CT scans. The clinical relevance of the mass effect exerted by intraventricular clots has recently been emphasized by Shapiro et al.19 According to their results, severe ventricular dilatation can be due to large amounts of blood distending the ventricle walls, independent of the obstruction of CSF pathways. They noted that hemorrhagic ventricular dilatation, especially of the fourth ventricle, is associated with a poor prognosis, most likely due to pressure on the brain stem impairing microcirculation, and that the prognosis is not improved by ventricular drainage.
Within 42 days after IVH, ventricular volume had returned to almost normal values in our study. This is a striking difference between our model and that of Pang et al,46 who reported that ventricular volume decreased slightly during the first week after IVH but then increased again during the third and fourth weeks after IVH and remained high until the end of follow-up (3 months). Persisting hydrocephalus was considered to be the consequence of impaired CSF absorption, but ICP and CSF dynamics were not assessed in their study. We cannot explain this difference between the two models. It is unlikely that the initial amount of intraventricular blood or the degree of ventricular dilatation played a role, since these parameters were very similar in the two studies.46 Based on data from the literature, we believe that the changes in ventricular volume produced by our model resemble adult human IVH very closely: previous studies suggest that adult IVH (in contrast to IVH in prematurely born infants) does not cause permanent hydrocephalus in the majority of the cases, provided that the hemorrhage is confined to the ventricular system.12 17 18 As expected, the incidence of permanent hydrocephalus is higher in IVH secondary to aneurysmal SAH, since SAH by itself causes impaired CSF absorption.41 42 43
Effect of TPA on Ventricular Dilatation
The present data demonstrate that TPA greatly accelerates the clearance of intraventricular blood in our porcine model. This effect became apparent as early as 1.5 hours after the initiation of TPA treatment. Accordingly, the compression of the ventricle walls decreased rapidly, which was paralleled by normalization of ventricular volume. It would appear from the preceding discussion that the elimination of the mass effect on the periventricular brain tissue, which has been identified as a major determinant of the outcome, might improve the prognosis of severe IVH. We did not measure Rout early after TPA injection, but it seems likely that the rapid reduction of the clot volume might also help to restore normal CSF circulation at the acute stage of IVH.
The ability of TPA to accelerate blood clearance in adult human IVH has been demonstrated by recent preliminary studies.25 26 27 28 It has been shown that fibrinolytic therapy, combined with external ventricular drainage, results in a substantial reduction of intraventricular blood and normalization of ventricle volume within 24 to 48 hours, even if the ventricles are subtotally filled with blood.26 Yet the hitherto existing clinical studies do not allow firm conclusions concerning either the impact of this new treatment modality on the patients' outcome or its safety because of the small size and heterogeneity of the study populations and the lack of untreated control groups. In the clinical setting, the assessment of benefits and risks of treatment is further impaired by the fact that adult IVH is most often associated with SAH or ICH, which overshadows the sequelae of intraventricular bleeding. Our IVH model might therefore be useful for the preclinical assessment of the efficacy and safety of TPA, as well as of other fibrinolytic agents, in the treatment of IVH under standardized conditions.
Conclusions
Our study suggests that the mass effect of clotted blood distending the ventricle walls is the main factor accounting for ventricular dilatation in severe IVH. An increase of outflow resistance due to obstruction of the CSF pathways may occur, especially at the acute stage of IVH. Accordingly, early ventricular drainage may be indicated to lower CSF pressure but will fail to remove the solid clots distending the ventricle walls. Rapid dissolution of the clots, reduction of compression of periventricular brain structures, and normalization of ventricular volume can be achieved by intraventricular TPA administration and might therefore improve the prognosis of IVH. Further experimental and clinical studies are necessary to determine the optimal dose and timing of TPA administration as well as the efficacy of fibrinolytic therapy on the overall clinical outcome after IVH. Our model closely imitates several prominent features of human IVH and may therefore be a useful tool for further experimental research on the pathophysiology and treatment of IVH.
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Acknowledgments |
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This study was supported in part by a grant from the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of the RWTH, Aachen, Germany. This work forms part of the doctoral thesis of Jenny Kissler (dissertation D82, RWTH, Aachen, Germany). We are grateful to Drs A. van Oosterhout and G. Brook for their comments and suggestions in editing the manuscript.
Received June 27, 1996; revision received October 9, 1996; accepted October 10, 1996.
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Editorial Comment
Characterization of Cerebrospinal Fluid Dynamics and the Effects of Fibrinolytic Treatment
Institute for Neurotrauma, Department of Neurosurgery, Wayne State University, School of Medicine, Detroit, Mich
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It came somewhat as a surprise to me how little experimental work has been done with primary (mostly) IVH. One of the reasons for this might be that in the past, management was not very controversial; ie, nothing could or needed to be done.
For the very same reason, primary IVH may have been thought of as uncommon: Patients were hospitalized for approximately 7 days, and 70 to 80% made an uneventful neurological, if not neuropsychological, recovery1R 2R and were subsequently forgotten. However, now that some form of therapeutic intervention is available, better statistics are being kept on these patients: In the past 2.5 years we saw 32 patients with primary IVH at Detroit Receiving Hospital who were treated with intraventricular injections of urokinase. This is approximately half the number of patients with aneurysmal SAH, but of those, almost half were transferred from other hospitals, while all the patients with IVH were admitted directly to Detroit Receiving Hospital. These figures probably indicate a higher incidence of primary IVH than hitherto thought (the same number of direct admissions as for aneurysmal SAH) and also a still persistent therapeutic nihilism (no transfer to neurosurgery).
The authors set out to answer the question of whether ventricular dilation is the result of impaired flow of CSF or of mass effect of the hematoma. They conclude it must be the latter, because at a time that CSF dynamics had normalized, there was still ventricular dilation, the extent of which was related to the size of the hematoma. I do not believe, however, that these conclusions can be drawn on the basis of the data presented. First, the amount of blood (10 mL) was always the same, and therefore the initial mass effect was supposedly also the same. To more firmly establish the influence of clot size and the time course of its resolution, different amounts of blood need to be injected and either left untreated or be treated with TPA at different times after the experimental hemorrhage. Second, the CSF dynamics were compared between treated and untreated animals only once, ie, on day 7. It may very well be that in the treated group, CSF dynamics had recovered much earlier than in the untreated group. If, for example, the authors would have performed the CSF dynamics tests on day 3, conclusions might have been totally different.
In this respect, it would also have been interesting if the authors had tested Rout by injection of saline into either the opposite ventricle or the spinal subarachnoid space. This would have indicated whether Rout is abnormal from factors prevalent mostly in the affected ventricle, in the whole ventricular system, or even outside the ventricles, such as pacchionian granulations. Third, the fact that CSF dynamics were practically normal on day 7, while the ventricles were still dilated, does not automatically mean that therefore the two are not related and ventricular size must be related to clot size. From the treatment of patients with hydrocephalus, we know that the ventricles can remain dilated for weeks or even months after insertion of a shunt. Finally, an argument against mass effect from the clot as the determining factor for hydrocephalus comes again from clinical practice. In many cases, the (large) clot is confined to only one lateral ventricle (which in itself is hard to understand), while the hydrocephalus is equally present in the contralateral ventricle without mass effect. A prime example of this can be found in Reference 2, figure 4a.
Despite the aforementioned differences of opinion, I still think that the authors have come up with a relevant model for IVH that could be useful for testing of new therapies.
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A value of P<.05 was considered significantly different from baseline values before IVH.
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1R. Darby DG, Donnan GA, Saling MA, Walsh KW, Bladin PF. Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology.. 1988;38:68-75.
2R. Gates PC, Barnett HJM, Vinters JV, Simonsen RL, Siu K. Primary intraventricular hemorrhage in adults. Stroke.. 1986;17:872-877.
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