Acta Neurochir (Wien) (1991) 108:116-121 :Acta Ndurochlrurgica �9 Springer-Verlag 1991 Printed in Austria

The Effects of Indomethacin on Intracranial Pressure, Cerebral Blood Flow and Cerebral Metabolism in Patients with Severe Head Injury and Intracranial Hypertension*

K. Jensen 1, J. I~hrstriim 2, G. E. Cold 3, and J. Astrup 4

~. 3 Department of Neuroanaesthesia and 2, 4 Department of Neurosurgery, A.rhus Kommunehospital, Denmark

Summary In five head-injured patients with cerebral contusion and oedema

in whom it was not possible to control intracranial pressure (ICP) (ICP > 20mmHg) by artificial hyperventilation (PaCO2 level 3.5-4.0 kPa) and barbiturate sedation, indomethacin was used as a vasoconstrictor drug. In all patients, indomethacin (a bolus injection of 30 mg, followed by 30 mg/h for seven hours) reduced ICP below 20 mmHg for several hours. Studies of cerebral circulation and me- tabolism during indomethacin treatment showed a decrease in CBF at 2h. After 7 h, ICP remained below 20mmHg in three patients, and these still had reduced CBF. In the other patients a return of ICP and CBF to pretreatment levels was observed. In all patients indomethacin treatment was followed by a fall in rectal temperature. These results suggest that indomethacin due to its cerebral vaso- constrictor and antipyretic effect should be considered as an alter- native for treatment of ICP-hypertension in head-injured patients.

Keywords: Acute head injury; barbiturate coma; cerebral blood flow; cerebral metabolism; hyperventilation; indomethacin; intra- cranial pressure; intracranial hypertension.

Introduction

Several studies in patients with severe head injury (HI) indicate that intracranial hypertension worsens the outcome, especially when ICP levels above 3 0 - 4 0 m m H g are recorded (Troup 1967, Vapalahti etaL 1969, Cold etal . 1975, Changaris etal . 1987). Other studies suggest that ICP-hypertension is the pri- mary reason for death in about 50% of patients with severe head injury (Miller et al. 1977, Miller et al. 1981).

Controlled hypervenfilation, barbiturate coma and mannitol treatment are generally recommended in pa- tients with threatening ICP-hypertension (Becker et al.

1977, Saul and Ducker 1982, Obrist et al. 1984), but it

* Presented at the Fifth Nordic CBF Symposium, Lund, Sweden, 21-22 May 1990.

is also well recognized that these therapeutic measures may fail to control ICP-hypertension making a search for other non-surgical intervention warranted.

In experimental (Pichard and MacKenzie 1973, Sak- abe and Siesj6 1979, Dahlgren etal. 1981) and clinical studies (Wennmalm et al. 1981, Wennmalm et al. 1984, Ohrstr6m etal . 1989) indomethacin, a prostaglandin inhibitor, acts as a cerebral vasoconstrictor and reduces CBF while the cerebral metabolism remains un- changed. Preliminary clinical studies in awake normal subjects have shown that the decrease in CBF during continuous indomethacin infusion is sustained during a 12h infusion period (Lassen and Jensen, personal communication).

This preliminary study reports on successful treat- ment with indomethacin of otherwise uncontrollable ICP-hypertension. The effects of indomethacin, ad- ministered i.v. over a 7 hours period were documented by measurements before and repeatedly during treat- ment of intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF), arterio-venous ox- ygen content difference (AVDO2) , arterio-venous lac- tate content difference (AVD(lactate)) and rectal tem- perature.

Material and Methods

Five males, median age 31 (range 22-42) with severe head injury were studied. Glasgow coma score at arrival was median 6, (range 5-7). On admission, CT showed bifrontal cerebral contusion in two patients, a left-sided parietal contusion in two and right-sided tem- pero-parietal contusion in one patient. Three patients were operated upon acutely for subdural and/or epidural haematoma. Repeated CT showed compression of the ventricular system and basal cisterns and progressive cerebral oedema in all patients.

K. Jensen et al.: The Effects of Indomethacin on Intracranial Pressure, Cerebral Blood Flow and Cerebral Metabolism 117

Medical Management of Patients with Severe Head Injury

After initial CT-scanning and possibly surgical decompression, a subdural screw, with a bottom plate and four side holes to prevent obstruction, was inserted for continuous ICP monitoring. MABP was continuously monitored intra-arterially. Pressures were recorded continuously on a two-channel recorder (Philips). The aims of treat- ment was to maintain ICP below 20mmHg, ensuring a minimum CPP of at least 70 mmHg (Rosner 1987). Dopamine was administered if necessary.

All patients were orally intubated, hyperventilated (PaCOz rang- ing from 4.0-4.5 kPa) and sedated with pentobarbitone in bolus doses of 50-100rag and morphine in doses of 10mg. Neurological ex- aminations were performed daily with special reference to evaluation of the conscious state (Glasgow coma score, GCS) and the brain- stem reflexes. CT's were repeated at daily intervals. If ICP-hyper- tension occurred (ICP > 20 mmHg for one hour) hyperventilation was intensified. If this was not sufficient to control ICP hypertension, the dose of pentobarbital was augmented to about 2 g/day. FinalIy, if ICP was still > 20mmHg for I-2 hours indomethacin treatment was started. Indomethacin was given as an initial bolus dose of 30 mg and a supplementary dose of 30 mg/h given continuously for 7 hours by infusion pump. Cimitidine treatment was initiated prior to the administration of indomethacin.

Before indomethacin treatment was initiated, all patients had in fact been hyperventilated to PaCQ 3.4 :I: 0.3 kPa (mean + SD), and were treated with pentobarbitone I00 mg/h for more than 12 hours. In addition, mannitol in doses of 0.5-I.0 g/kg was used.

The protocol was approved by the local ethical committee.

The Measurement of Regional Cerebral Blood Flow (rCBF) and Ce- rebral Metabolism

rCBF was measured at the bedside with a 10 channel Cerebro- graph (Novo Cerebrograph 10 a) with 5 detectors placed on each side over the parieto-temporal regions, rCBF was calculated as CBF- 15 and CBF-ISI. A V D O 2 w a s calculated as the difference of oxygen content between arterial and jugular venous blood (ABL 3 Radi- ometer and OSM 3 Radiometer, Copenhagen). CMRO2 was cal- culated as the product of the average CBF-15 and AVDO2. Arterial and venous blood was sampled in fluoride tubes and plasma stored - 20 ~ until measurement of lactate had been completed. The lac- tate/oxygen index (LOI) defined as - AVD(lactate)/AVDO2 was cal- culated (Robertson etal. 1989).

The CBF measurements were performed immediately before in- domethacin administration and 15 min, 2h, 4h and 7 h during in- domethacin infusion. The measurement of AVDO2 and AVD(lactate) was performed simultaneously with the CBF meas- urements.

Mean values and SD were calculated. The one sided Sign-tests were used for statistical analyses. A p < 0.05 was considered sig- nificant.

Results

Indomethacin treatment was started the second day after the trauma in three patients, and on the third day in 2 patients.

Changes in ICP

In all 5 patients the bolus injection of indomethacin (30rag) was followed by a decrease in ICP starting

5 10 sec after injection. The minimum ICP level was reached within 1-5 rain. Within 15 min indomethacin resulted in a decrease in ICP from 28 • 3 to 17 • 6 (Fig. 1). This decrease in ICP lasted about 4 hours and was followed by an increase in ICP which after 7 h treatment was 25 + 11 mmHg. In Fig. 2 the recordings of ICP before and during indomethacin treatment are shown. The ICP values were averaged over 5 rain from 3 hours before to 7 hours after indomethacin treatment.

Changes in CBF, Arterio-venous Difference of Oxygen (AVDOe) and Cerebral Metabolic Rate of Oxygen (CMROe)

15 min after bolus injection of indomethacin a de- crease in CBF-ISI (mean CBF of 10 detectors) were found in four of five patients. At 2 h the decrease in CBF-ISI was significant with a decrease from 34 :L 9

MABP: 90 ram Hg , , /

70

lOP: 40n

0 ~- 2 0 m i n -~

Fig. l. Changes i n intracranial pressure (1CP, mmHg) and mean arterial blood pressure (MABP, mmHg) before and after a bolus injection of indomethacin 30rag

50

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Indomethacin Time (hours)

Fig. 2. Intracranial pressure (ICP, mmHg) in five patients subjected to indomethacin treatment (30 mg i.v., followed by 30 mg/h for 7 hours). The ICP values are averaged over 5 min at time 3, 2, I h and 0 before indomethacin and at time 15 rain, 2 h, 3 h, 4 h, 5 h, 6 h and 7 h after treatment. The mean values of the 5 patients are indicated

118 K. Jensen etal.: The Effects of Indomethacin on Intracranial Pressure, Cerebral Blood Flow and Cerebral Metabolism

50

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Time (hours)

Fig. 3. CBF-ISI (ml/100g/min) in five patients subjected to indo-

methacin t reatment (30rag i.v., followed by 30mg/h for 7 hours).

CBF are measured at time 15 min before and at 15 rain, 2 h, 4 h, and

7 h after indomethacin treatment. The mean values of the 5 patients

are indicated

40 \ \ \ .

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~38 = ~ = ..... . . . . . . "---=~"~>::<.~.__.~....~ .............

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~' I n d o m e t h a c i n T i m e ( h o u r s )

Fig. 4. Rectal temperature (~ in five patients subjected to indo-

methacin treatment (30rag i.v., followed by 30mg/h for 7h). The

mean values are indicated

to 25 4- 9ml/100g/min (p < 0.05). The decrease in CBF was accompanied by an increase in AVDO2 (p < 0.05). The level of CMRO2 remained stable during the treatment period and did not differ from the pre- treatment level. The level of C M R O 2 did not change from the pre-treatment level. The level of CMRO2 did not change significantly. However, in one patient a fall in rectal temperature from 39.9 to 36.8 ~ during the treatment period was accompanied by a decrease in CMRO2 from 2.0 to 1.4ml O2/100g/min. Fig. 3 indi-

cates the changes in CBF-ISI in the 5 patients. The changes in AVDO2 and CMRO2 are shown in Table 1.

Changes in Arterio-venous Difference of Lactate (AVD(Lactate) and the Lactate/Oxygen Index (LOI)

15rain after indomethacin bolus injection an in- crease in AVD(lactate) from - 0.13 4- 0.03 to

- 0.18 4- 0.05 was observed (p < 0.05). This change was not accompanied by a significant increase in LOI.

Table 1. Studies of PaCOe (kPa), Cerebral Perfusion Pressure (CPP, mm Hg), Intracranial Pressure (ICP, mm Hg), CBF-ISI (ml/lOO g/min, Arterio-Venous Oxygen Difference (A VD02, mmol/l), Cerebral Metabolic Rate of Oxygen (CMRO~, ml2/100 g/rain), Arterio-Venous Difference of Lactate ( A VD (Lactate), mmol/l), Lactate~Oxygen Index (-A VD( Lactate) /A VD0 2) and RectaI Temperature (~ Celsius). The CBF studies

were performed 15rain before and at time 15min, 2h, 4h , and 7h during indomethacin treatment (30rag i.v. followed by 30mg/h for 7h). Mean values 4- SD are indicated

- 15 min 15 rain 2 hours 4 hours 7 hours

PaCOz (kPa) 3.44- 0.3 3.34- 0.4 3.3 4- 0.5 3.3 4- 0.4 3.4 + 0.4

CPP (ram Hg) 804- 13 894- 15 854- 10 764-6 724-9 ICP (ram Hg) 284-3 174-6" 214-4 184-4" 254-11

CBF-ISI (ml(100 g/rain) 34 4- 9 29 4- 11 25 • 9* 28 4- 7 27 • 9

AVDOz (mmol/1) 2.5 4- 0.6 3.0 4- 0.4 3.1 4- 0.2* 3.0 4- 0.4 3.0 4- 0.9

CMRO2 (ml 2/100 g/min) 1.9 4- 0.5 1.9 4- 0.6 1.8 4- 0.4 2.0 4- 0.3 1.8 4- 0.9 AVD (lactate) (mmol/1) -0 .134-0 .03 - 0 . 1 8 4 - 0 . 0 4 ' - 0 . 0 8 ~ 0 . 0 9 - 0 . 0 9 • - 0 . 1 0 • Lactate/oxygen index (LOI) 0.05 4- 0.01 0.06 4- 0.02 0.03 • 0.03 0.03 4- 0.01 0.04 4- 0.04 Rectal temp. (Celsius) 38.6 + 0.8 38.5 i 0.7 38.1 4- 0.5" 37.6 4- 0.4* 37.3 4- 0.4*

* P<O.05.

K. Jensen etal.: The Effects of Indomethacin on Intracranial Pressure, Cerebral Blood Flow and Cerebra1 Metabolism 119

The changes in AVD(lactate) and LOI are shown in Table 1.

Changes in Rectal Temperature

Within the treatment period a fall in rectal temper- ature from 38.6 • 0.8 to 37.3 • 0.4 was observed. The changes in rectal temperature are shown in Fig. 4.

Outcome

Presently, 1-6 months have passed since the injury. All patients recovered consciousness and orientation. Outcome scaling has not yet been performed.

Discussion

UncontrollaNe ICP-hypertension is well recognized as a main cause of death in patients with severe HI (Miller etal. 1977, Miller etal. 1981). This study pre- sents five patients with uncontrollable ICP-hyperten- sion in spite of hyperventilation to PaCO2 about 3.5 kPa and pentobarbitone sedation with doses about 2 g/24 hours. In addition mannitol was used without lasting effect in four patients. Clearly, alternative or additional modes of treatment are searched for in this threatening clinical condition. Indomethacin was cho- sen since clinical and experimental studies have shown that indomethacin, like hypocapnia, acts as a cerebral vasoconstrictor and reduces CBF while CMRO 2 re- mains unchanged (Pichard and MacKenzie 1973, Sak- abe and Siesj6 1979, Dahlgren etal. 1981, Wennmalm etal. 1981, Wennmalm etal. 1984, Ohrstr6m etal.

1989). Indomethacin is a blocker of fatty acid cyclo- oxygenase and thereby prostaglandin synthesis. Ex- perimental studies of canine basilar arteries indicate that indomethacin potentiates the contractile responses produced by prostaglandin F 2 (Kanamaru et al. 1987). Experimental studies of traumatic brain injury suggest that prostaglandins mediate cerebral ocdema (Shohami etal. 1987), and in cats subjected to focal ischaemia (Dempsey etal. 1985) and rats subjected to freezing lesions (Yen and Lee 1987), indomethacin reduces cer- ebral oedema. Other experimental studies indicate that indomethacin reduces cerebral infarct size in focal is- chaemia (Sasaki et al. 1988), enhances post-ischaemic re-perfusion after middle cerebral artery occlusion (Shi- geno et al. 1985) and reduces cerebral fluid compression (Hallenbeck and Furlow 1979). Furthermore, in rats subjected to fluid percussion trauma pre-treatment with indomethacin improves recovery (Kim etal. 1989). However, these effects are debated. Thus, in other ex- perimental studies of focal ischaemia (Harris et al. 1982,

Awad etal. 1983, Sutherland etal. 1988, Suzuka etal.

1989) and traumatic head injury (Shapira et al. 1988), indomethacin administration was not followed by a decrease in cerebral oedema. Other experimental stud- ies suggest that the infarct size in focal cerebral is- chaemia was not influenced by indomethacin (Harris etal. 1982, Koide etal. 1986).

In the present study, indomethacin caused a signif- icant fall in ICP within a few minutes and lasting several hours. The results suggest that this effect is explained by a vasoconstrictor effect of indomethacin and a fall in CBF. This effect may be explained as a direct effect of indomethacin on cerebral arterioles, but part of the effect may be mediated through the antipyretic effect of indomethacin, in particular in the cases of severe hyperpyrexia as described by Benedek etal. (1987). Overall, CMRO2 did not change significantly, indi- cating that the main effect of indomethacin is a va- soconstrictor effect accounting for the fall in CBF and ICP without significant changes in CMRO2. However, in one hyperpyretic patient a fall in rectal temperature from 39.9 to 36.8 ~ was associated with a decrease in ICP and CBF, and a fall in C M R Q from 2.0 to 1.4ml O2/100 g/rain.

The results of this study suggest that indomethacin has a direct vasoconstrictor effect on the cerebral ves- sels in the head injured patient. Similar to the problem if hyperventilation causes cerebral ischaemia, it should be asked ifindomethacin induced vasoconstriction may cause ischaemia. Ischaemia would be indicated by a further fall in CMRO 2 and a net production of lactate in relation to oxygen uptake as indicated by an in- creasing AVD(lactate) and LOI. No such significant changes were observed although CBF in one patients fell below 20 ml/100 g/rain, otherwise considered to be the threshold of synaptic function and in the normal brain associated with lactic acid acidosis. In no case did LOI increase above 0.08, which according to Rob- ertson et al. (1989) is the limit for ischaemic infarction as evaluated by CT-scanning. Certainly, the vasocon- strictor effect of indomethacin with its potential danger of focal or more diffuse cerebral ischaemia needs fur- ther clarification.

Recently, the prophylactic use of barbiturate coma and controlled hyperventilation in the treatment of se- vere HI have been questioned. According to studies by Ward et al. (1985) barbiturate coma-treatment worsens the clinical outcome and further investigations suggest that controlled hyperventilation used prophylactically does not improve outcome but prolongs the recovery phase (Ward et al. 1989). Accordingly, alternative and

120 K. Jensen etal.: The Effects of Indomethacin on Intracranial Pressure, Cerebral Blood Flow and Cerebral Metabolism

additional treatment of ICP-hypertension should be considered. In this context, this preliminary report of a beneficial effect of indomethacin on ICP-hyperten- sion, cerebral circulation and metabolism is promising. However, a number of questions concerning indo- methacin therapy and its effects on cerebral haemo- dynamics in head injured patients are yet unanswered. Its vasoconstrictor effect and potential danger for cer- ebral ischaemia demands caution and must be further studied in relation to the effect on ICP. The relationship between CO2 reactivity and response of cerebral cir- culation to indomethacin should be studied. Finally, our results indicate adaptation of the response on cer- ebral circulation with time, and this phenomenon should be further studied in relation to a possible dose- response correlation, and the question of the appro- priate dose of indomethacin.

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Correspondence and Reprints: Georg Emil Cold, Department of Neuroanaesthesia, ~rhus Kommunehospital, ~rhus DK-8000, Denmark.