Reduction of vasopressor requirement by hydrocortisone administration in a patient with cerebral vasospasm

J. A. Alhashemi

Division of Critical Care Medicine, London Health Sciences Centre – University Campus, University of Western Ontario, London, Ontario, Canada N6A 5A5. Present Address: Department of Anesthesia & Critical Care, King Abdulaziz University Hospital, King Abdulaziz University, PO Box 31648, Jeddah 21418, Saudi Arabia

Accepted for publication: August 17, 2000


    Abstract
 Top
 Abstract
 Introduction
 Case history
 Discussion
 References
 
A 67-yr-old female received hypertensive, hypervolaemic treatment for cerebral vasospasm after severe subarachnoid haemorrhage. After 3 days of continuous vasopressor infusion and despite adequate hydration and normal cardiac function, the phenylephrine dose had to be increased to obtain the same systolic blood pressure. This tachyphylaxis to phenylephrine infusion was probably caused by down-regulation of {alpha} adrenoceptors, and was reversed by giving i.v. hydrocortisone.

Br J Anaesth 2001; 86: 138–41

Keywords: sympathetic nervous system, phenylephrine; receptors, adrenergic; complications, tachyphylaxis


    Introduction
 Top
 Abstract
 Introduction
 Case history
 Discussion
 References
 
Vasoactive drugs are used to induce hypertension in patients with subarachnoid haemorrhage (SAH) who develop cerebral vasospasm and are being treated with triple-H therapy (hypertension, hypervolaemia and haemodilution).1 This treatment is often needed for up to 2 weeks, beyond which time clinical vasospasm is rarely observed.2 Prolonged administration of adrenoceptor agonists has been associated with decreased adrenoreceptor density,3 4 which may increase the need for these drugs to achieve the same induced hypertension.5 In this report, hydrocortisone reversed the increased dose requirement for phenylephrine in a patient with cerebral vasospasm. This is the first report of the use of hydrocortisone for tachyphylaxis.


    Case history
 Top
 Abstract
 Introduction
 Case history
 Discussion
 References
 
A 67-yr-old otherwise healthy woman presented with Hunt and Hess’ grade 4 SAH6 (World Federation of Neurosurgical Surgeons grade 5 haemorrhage) and was immediately admitted to the intensive care unit (ICU) for management (day 0 after SAH). Her heart rate was 110 min–1, arterial pressure 120/75 mm Hg, and Glasgow Coma Scale score 6. The trachea was intubated and mechanical ventilation with pressure support of 10 cm H2O, PEEP (positive end-expiratory pressure) of 5 cm H2O and FIO2 of 0.40 was started. Computed tomography (CT) scanning of her brain showed blood in the basal cisterns, sulci, sylvian fissure, anterior falx and the lateral ventricles, but there was no evidence of hydrocephalus. Arterial and central venous catheters were inserted for invasive pressure monitoring, and the patient was given normal saline. Several hours after her presentation and admission to the ICU, the patient was opening her eyes to voice and following commands with her right side but had left hemiparesis. She was not hyperventilated and her arterial blood gases were normal throughout the course of her ICU stay. One day after the SAH, a cerebral angiogram showed anterior communicating and left posterior communicating artery aneurysms without evidence of cerebral vessels narrowing. She was given oral nimodipine 60 mg every 4 h. Four days later coils were placed in both aneurysms. The patient’s neurological state did not change. On day 6, a baseline transcranial Doppler (TCD) examination showed no cerebral vasospasm, with a mean flow velocity in the middle cerebral arteries (MCA) of 110 cm s–1. On day 7, the patient’s level of consciousness decreased despite maintenance of normal arterial pressure (130/80 mm Hg), adequate urine output (>0.5 ml kg–1 h–1) and satisfactory central venous pressure (CVP) of 10 mm Hg. She could localize stimuli with her right upper arm and withdrew her right leg on stimulation. A repeat TCD examination showed that mean flow velocity had increased to 139 cm s–1 in the left MCA. Phenylephrine infusion was started at 100 µg min–1 to maintain systolic blood pressure (SBP) at 170–190 mm Hg. The neurological state rapidly improved after the target SBP was achieved with the phenylephrine infusion. In addition to the hypertensive therapy, i.v. hydration with normal saline and intermittent doses of pentastarch were given to keep the CVP >=12 mm Hg. A pulmonary artery catheter was inserted. The cardiac index was 4.11 litre min–1 m–2, pulmonary artery occlusion pressure (PAOP) 15 mm Hg, and CVP 15 mm Hg. A repeat cerebral angiogram on the 8th day after SAH showed minimal left MCA vasospasm, although a quantitative measure of the vessel diameter was not available. Nevertheless, the triple-H therapy was continued because of the clinical evidence of continuing cerebral vasospasm.

Despite the maintenance of adequate hydration (CVP and PAOP >=12 mm Hg) and the presence of normal cardiac function (cardiac index >=4.0 litre min–1 m–2), the phenylephrine dose had to be increased 3 days after starting the vasopressor therapy to maintain the same initial target SBP of 170–190 mm Hg. There was no clinical or laboratory evidence of infection, renal dysfunction or acid–base disturbance at any time. The patient continued to have clinical evidence of cerebral vasospasm as her conscious state consistently deteriorated and then rapidly returned to normal whenever her SBP decreased below 170 mm Hg and was then restored. These transient episodes of relative hypotension occurred in relation to medication bag replacement and after nimodipine administration. The nimodipine dose was halved and then discontinued because hypotension occurred after each dose of nimodipine. On day 14 after SAH, a morning serum cortisol sample was taken and hydrocortisone 100 mg i.v. every 8 h was started, with a consequent reduction in phenylephrine infusion rate from a maximum of 2000 µg min–1 to 800 µg min–1. This decrease in vasopressor requirement occurred after three doses of hydrocortisone and without changing the target SBP (Fig. 1). The serum cortisol concentration was 566 nmol litre–1 (normal range 119–618 nmol litre–1) and the patient maintained normal acid–base and renal function. Phenylephrine dose requirement continued to decline to 50–100 µg min–1, to give an SBP of 170–190 mm Hg. After five doses, hydrocortisone was discontinued without any increase in phenylephrine dose requirement or any change in the target SBP. On day 17 after the SAH, the phenylephrine infusion rate was gradually decreased and then stopped. The SBP returned to 140 mm Hg without any change in the patient’s condition. On day 18 after the SAH, the patient was discharged from the ICU, with persistent left hemiparesis.



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Fig 1 Changes in phenylephrine requirement and systolic arterial pressure. The solid and open arrows represent the first and last doses of hydrocortisone respectively.

 

    Discussion
 Top
 Abstract
 Introduction
 Case history
 Discussion
 References
 
Adrenoceptor agonists such as phenylephrine and norepinephrine are used to cause hypertension in patients with cerebral vasospasm after SAH. These drugs are usually given for up 2 weeks after the onset of vasospasm, which can decrease responsiveness to these vasoactive agents. In animal studies, adrenoceptor down-regulation and decreased responsiveness occur when catecholamines are given in large doses and/or for long periods.79 Similar findings occur in human subjects.1012 In this report, phenylephrine was infused for three days before a progressive increase in dose requirement, to achieve the same target blood pressure, was observed (Fig.1). The haemodynamic values measured by the pulmonary artery catheter indicated that adequate hydration and normal cardiac function were maintained. Down-regulation of {alpha} adrenoceptors is the likely explanation for the observed increase in phenylephrine dose requirement. Although previous reports have documented ß receptor down-regulation in relation to prolonged exposure to ß agonists,712 the findings of this report suggest that selective down-regulation may also involve {alpha} adrenoceptors. This has not been reported previously.

Although receptor reappearance has been described after stopping the adrenoceptor agonist,13 withholding phenylephrine was not possible in this patient because of persistent cerebral vasospasm, shown by the reproducible deterioration in the patient’s level of consciousness whenever her SBP decreased below 170 mm Hg, during medication bag replacement and after nimodipine administration. Halving the dose of nimodipine did not affect the decrease in SBP, with a concomitant deterioration in the patient’s level of consciousness after the administration of each dose of the drug. Corticosteroids prevent homologous down-regulation of ß2 receptors14 and up-regulate lymphocyte ß receptors.15 16 In addition, Aziz et al.17 have reported that inhaled budesonide resensitizes the cardiac ß2 receptor response to salbutamol in patients treated with long-acting ß2 agonists. Bollaert et al.18 described an improvement in the haemodynamic profile of patients with late septic shock who were treated with hydrocortisone in the absence of adrenal insufficiency. In this case report, vasopressor requirements were reduced by 50% within 12 h of hydrocortisone administration (Fig. 1), with no change in the patient’s CVP, PAOP or cardiac index, and with no clinical or laboratory evidence of adrenal insufficiency, acid–base disorder or renal dysfunction. On the basis of the study of Bollaert et al.18 and because the phenylephrine dose requirement decreased to a reasonable level of 50–100 µg min–1, hydrocortisone was stopped after five doses of the drug.

Although steroid-induced up-regulation of the {alpha} adrenoceptors is one possible explanation for the decrease in phenylephrine requirement, another potentially plausible explanation is steroid-induced inhibition of nitric oxide synthase (NOS). Inhibition of this enzyme decreases endogenous production of nitric oxide (NO), a potent vasodilator that has been implicated in vascular hyporeactivity. This potential mechanism is supported by the findings of Szabo et al.,19 who found that NO-induced vascular hyporeactivity was reduced after dexamethasone, an NOS inhibitor. Similar findings were observed by Thiemermann and colleagues in rats with haemorrhagic shock.20 Whether the administration of large doses of phenylephrine induces the enzyme NOS is an intriguing question, but steroid-induced NOS inhibition has been shown only in animals. Future human studies are needed.

In conclusion, this case report demonstrated that short-term i.v. hydrocortisone decreased the escalating phenylephrine dose requirements in a patient with SAH who was being treated with induced hypertension to counteract cerebral vasospasm. Although {alpha} adrenoceptor up-regulation in response to steroid therapy is a plausible explanation, the exact mechanism of the steroid-induced reduction in vasopressor requirement remains undetermined. Studies on the effect of steroids on vascular hyporeactivity in response to prolonged administration of an adrenoceptor agonist are warranted.


    References
 Top
 Abstract
 Introduction
 Case history
 Discussion
 References
 
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20 Thiemermann C, Szabo C, Mitchell JA, Vane JR. Vascular hyporeactivity to vasoconstrictor agents and haemodynamic decompensation in haemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci USA 1993; 90: 267–71[Abstract]





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