Non-conventional Therapeutics for the Treatment of Elevated Intracranial Pressure: Indomethacin and THAM

29 Non-conventional Therapeutics for the Treatment of Elevated Intracranial Pressure: Indomethacin and THAM

Madds Rasmussen ¹, Alberto Biestro ²

¹ Department of Neuroanesthesia, Århus University Hospital, Nørrebrogade 44, 8000 Århus C., Denmark

² Professor alone de Medicina a Intensiva, Intensive Care Center Hospital de Clinicas Montevideo, Uruguay

29.1 Indomethacin

Indomethacin, a non-selective fatty acid cyclo-oxygenase inhibitor, is a potent cerebral vasoconstrictor and decreases cerebral blood flow (CBF) without affecting cerebral oxygen metabolism in experimental and clinical studies. Indomethacin’s action on cerebrovascular physiology is unique and does not appear to be shared by other cyclo-oxygenase inhibitors.

Published clinical experience with indomethacin in the management of elevated intracranial pressure (ICP) in head-injured patients is limited to six small uncontrolled studies. In order to provide the clinician with sufficient information on the use of indomethacin as a treatment option, the following section presents a short review of the literature on clinical experience with indomethacin in controlling ICP.

29.1.1 Literature Review

Jensen et al. treated five patients with severe head injury and elevated ICP. Indomethacin was administered as bolus of 30 mg IV, followed by infusion of 30 mg/h for 7 hours when ICP was >20 mmHg despite treatment with hyperventilation, pentobarbitone and mannitol [1]. Intracranial pressure decreased within 5-10 seconds after administration and reached a minimum 1-5 minutes after indomethacin administration; and within 15 minutes, the mean ICP decreased from 28 to 17 mmHg. This decrease in ICP lasted about 4 hours and was followed by an increase in ICP after 7 hours. The reduction in ICP was accompanied by a non-significant increase in cerebral perfusion pressure (CPP) and an average decrease in CBF from 34 to 29 ml/100 g/min, measured 15 minutes after initiation of treatment. The pronounced effect of indomethacin in lowering ICP was later confirmed in an uncontrolled study by Biestro et al. who treated 10 patients with severe head injury and elevated ICP refractory to treatment with mannitol, hyperventilation and barbiturates [2]. Indomethacin was administered as a bolus dose of 50 mg IV over 20 minutes, followed by continuous infusion of 21.5±11 mg/h over 30±9 hours. Mean ICP was reduced from 34.4 to 16.4 mmHg and associated with an increase in CPP. Intracranial pressure (average, 23.1 mmHg) remained decreased during the infusion. Subsequent discontinuation of indomethacin treatment resulted in a significant rebound of ICP to pre-treatment levels. The authors did not measure CBF or cerebral metabolic rate of oxygen (CMRO₂) [2].

In another study of patients with severe head injury, Dahl et al. found that the decrease in ICP following an indomethacin bolus dose of 30 mg was comparable to the ICP decrease observed during a 0.88 kPa decrease in partial pressure of carbon dioxide in arterial blood (paCO₂) [3]. However, as compared to hyperventilation, the authors reported that indomethacin administration was accompanied by a more pronounced decrease in CBF and a significant increase in both mean arterial blood pressure (MABP) and CPP.

Imberti et al. demonstrated in 9 patients with severe head injury or intraparenchymal hemorrhage that indomethacin (bolus of 15-20 mg) is effective in extinguishing plateau waves (sudden and steep increases in ICP due to cerebral injury) [4]. They found that ICP decreased from an initial average of 58 to 21.2 and 25.8 mmHg after 5 and 10 minutes, respectively. Also, they found an increase in brain tissue oxygen partial pressure (PO₂), CPP and arteriojugular venous difference of oxygen (AVDO₂) without changes in MABP.

Recently, Puppo et al. demonstrated in 16 patients with severe head injury that indomethacin significantly reduced ICP and CBF and increased CPP. Their study also suggested that indomethacin may improve dynamic cerebral autoregulation [5].

29.1.2 Dose Considerations

The bolus dose of indomethacin used in clinical studies ranges from 0.1 to 0.5 mg/kg. Infusion rates range from 22 over 30 hours to 30/h mg over 7 hours.

29.1.3 Adverse Effects

The vasoconstrictive effect of indomethacin may increase the risk of cerebral ischemia in head-injured patients with compromised CBF. No studies have evaluated the risk of indomethacin-induced cerebral ischemia in patients with head injury. Currently, no adverse effects have been reported. However, reductions in CBF after indomethacin administration were reported in the above-mentioned studies and it is possible that some of these patients suffered from cerebral hypoperfusion.

Indomethacin does extend bleeding time but not beyond the normal range in healthy volunteers. It is possible that indomethacin may increase the risk of bleeding in coagulapathic patients.

Care should be taken with the use of indomethacin in patients with compromised renal function, and the drug may also have an adverse effect on renal function in hypovolemic patients.

29.1.4 Summary and Recommendations for the Use of Indomethacin

Evidence for the use of indomethacin in the treatment of elevated ICP is scarce. In a small number of uncontrolled studies, indomethacin has been demonstrated to effectively reduce ICP and improve CPP in patients with severe head injury. Therefore, we only recommend it as a therapeutic option to reduce increases in ICP when conventional therapy has failed. We suggest the following treatment protocol in the sedated, mechanically ventilated patient with severe head injury (Glasgow Coma Scale [GCS] <8):

Elevated ICP >20 mmHg for 1-2 hours despite conventional ICP-reducing therapy. Surgical explanations for persistent high ICP should be eliminated.
Administer indomethacin as a bolus dose of 0.1 mg/kg followed by infusion of 0.1 mg/kg/h. Monitor ICP if possible and repeatedly re-evaluate the patient and reconsider the need for indomethacin. We suggest that indomethacin infusion be terminated after a maximum of 30 hours.
A central venous catheter should be placed in the jugular bulb to monitor the effect of indomethacin on CBF. Jugular bulb oxygen saturation (SjVO₂) <50 % may indicate cerebral hypoperfusion and increase the risk of cerebral ischemia.

29.2 Tromethamine (THAM or TRIS)

In our experience, THAM is a alternative option for the treatment of refractory intracranial hypertension (ICH). The drug acts on the main mechanisms of ICH: 1) derangement in cerebrovascular reactivity; and 2) lowering of spatial buffering.

Like indomethacin, it is a low-cost, easily managed drug with a good benefit/risk ratio.

29.2.1 Pharmacological Properties

THAM is a stable, hydrophilic alcohol amine that behaves as a weak base and can buffer metabolic and respiratory acidosis (formulas 1 and 2, respectively). Along with carbicarb, it is the only compound in clinical use with the property to reduce carbon dioxide content in the blood.

THAM-R-NH₂ + H⁺ + La^– ↔ THAM-R-NH₃⁺ + La^– (Formula 1)

THAM-R-NH₂ + H₂O + CO₂ ↔ THAM-R-NH₃⁺ + HCO₃ (Formula 2)

The formulation currently used is a 0.3 molar solution of THAM acetate (mol/l) with the following properties:

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