Management of life-threatening autonomic hyper-reflexia using magnesium sulphate in a patient with a high spinal cord injury in the intensive care unit

N. A. Jones*,1 and S. D. Jones2

1Department of Anaesthesia and Intensive Care, North Hampshire Hospital, Basingstoke, UK. 2Northern Schools of Anaesthesia Newcastle, Royal Victoria Infirmary, Newcastle upon Tyne, UK*Corresponding author. Present address: Department of Anaesthesia and Pain Management, Royal Perth Hospital, Perth 6000, Western Australia

Accepted for publication: October 22, 2001


    Abstract
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
We report the successful use of i.v. magnesium sulphate to control life-threatening autonomic hyper-reflexia associated with chronic spinal cord injury in the intensive care environment. A 37-yr-old, male was admitted to the intensive care unit with a diagnosis of septic shock and acute renal failure secondary to pyelonephritis. He had been found unresponsive at home following a 2-day history of pyrexia and purulent discharge from his suprapubic catheter. He had sustained a T5 spinal cord transection 20 yr previously. Initial management included assisted ventilation, fluid resuscitation, vasopressor support, and continuous veno-venous haemofiltration. The sepsis was treated with antibiotic therapy and percutaneous nephrostomy drainage of the pyonephrosis. On the fifth day, the patient developed profuse diarrhoea. This was associated with paroxysms of systemic hypertension and diaphoresis, his arterial pressure rising on occasion to 240/140 mm Hg. A diagnosis of autonomic hyper-reflexia was made and a bolus dose of magnesium sulphate 5 g was administered over 15 min followed by an infusion of 1–2 g h–1. There was an almost immediate decrease in the severity and frequency of the hypertensive episodes. There were no adverse cardiac effects associated with the administration of magnesium, only a slight decrease in minute ventilation as the plasma level approached the upper end of the therapeutic range (2–4 mmol litre–1). In view of the beneficial effects observed in this case we advocate further research into the use of magnesium sulphate in the treatment or prevention of autonomic hyper-reflexia secondary to chronic spinal cord injury in the intensive care unit.

Br J Anaesth 2002; 88: 434–8

Keywords: complications, autonomic hyper-reflexia; complications, spinal cord injury; pharmacology, magnesium sulphate; intensive care


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Autonomic hyper-reflexia is a common and potentially life-threatening complication of chronic spinal cord injury and its control is paramount to the safe care of such patients in the intensive care environment. Intravenous magnesium sulphate has proven useful in controlling paroxysmal hypertension associated with tetanus and phaeochromocytoma.1 In view of its pharmacological mode of action there is scientific rationale for the use of magnesium in controlling the hypertensive crises of autonomic hyper-reflexia in intensive care.


    Case report
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
A 37-yr-old, 128 kg, Caucasian male was referred to the intensive care unit having been found unresponsive at home following a 2-day history of pyrexia, myalgia, and an offensive discharge from his suprapubic catheter. He had sustained a T5 spinal cord transection in a road traffic accident 20 yr previously that had left him paraplegic. Subsequent recurrent urinary tract infections had led to a hypotrophic, non-functioning right kidney, and multiple perinephric abscesses involving the left kidney, for which he had undergone a left partial nephrectomy 4 yr previously. His serum creatinine concentration was normal at 96 µmol litre–1, 6 months before this admission. His history was further complicated by mild asthma and diet-controlled non-insulin-dependent diabetes mellitus. His medication included oral dantrolene 50 mg three times daily and baclofen 10 mg three times daily for muscle spasms, he controlled the headaches associated with autonomic hyper-reflexia with nitroglycerine sublingual spray.

On presentation he had a Glasgow Coma Scale of 4, which improved to 9 with i.v. fluid resuscitation, a tympanic temperature of 38.2°C, a sinus tachycardia of 122 min–1 and he was hypotensive (arterial pressure 75/32 mm Hg). He had a neutrophil leucocytosis (24.0x109 litre–1), a C-reactive protein concentration of 270 mg litre–1, a blood glucose concentration of 22.6 mmol litre–1, and a base excess of –12. In addition, he was anuric with a serum creatinine concentration of 346 µmol litre–1. An ultrasound scan revealed an absent right kidney, left hydronephrosis, and an empty bladder. A diagnosis of septic shock secondary to pyelonephritis was made and following blood culture the patient was commenced on cefotaxime 1 g three times daily, metronidazole 500 mg twice daily, and gentamicin 4 mg kg–1, the dosing interval being dictated by daily serum gentamicin assays.

Intravenous fluid resuscitation was continued, the airway was secured by orotracheal intubation and artificial ventilation assisted using synchronized intermittent mandatory ventilation with pressure support. Continuous veno-venous haemofiltration was commenced and systolic arterial pressure was maintained above 100 mm Hg with i.v. fluid and norepinephrine 0.015 µg kg–1 min–1. Insulin was commenced at 4 units h–1 to control blood glucose levels and sedation was maintained with propofol 180 mg h–1 and fentanyl 100 µg h–1. Once the patient was stable haemodynamically, a left-sided nephrostomy tube was inserted percutaneously under ultrasound guidance. Blood and urine cultures grew Enterococci and Proteus spp.

The patient made good progress and by the fourth day after admission no longer required vasopressor support and was polyuric through the nephrostomy. His white cell count and serum creatinine concentration had fallen to 9.0x109 litre–1 and 215 µmol litre–1, respectively. Continuous veno-venous haemofiltration was discontinued.

On the fifth day, the patient developed profuse diarrhoea. Shortly afterwards, unpredictable and sudden paroxysms of systemic hypertension started, the arterial blood pressure reaching 240/140 mm Hg on occasion. These episodes were associated with pallor and diaphoresis. The heart rate remained largely unchanged. Rising serum glucose levels were treated by adjusting the continuous i.v. infusion of insulin, which was increased from 4 to 8 units h–1. A diagnosis of autonomic hyper-reflexia was made and sedation was increased such that the patient just coughed on suctioning. Nevertheless, paroxysms of hypertension increased in frequency and severity over the following 24 h. They were thought to be triggered by visceral stimulation associated with the diarrhoeal illness. A bolus dose of magnesium sulphate 5 g (approximately 40 mg kg–1) was administered by slow i.v. injection over a 15-min period with continuous ECG and invasive arterial pressure monitoring. This was followed by an infusion of magnesium sulphate at 1–2 g h–1 with the aim of achieving a plasma concentration of 2–4 mmol litre–1.1 A decrease in both the frequency and severity of the systolic hypertensive episodes was noted almost immediately (Table 1).


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Table 1 The maximum, minimum and median systolic pressures over 10 4-h periods before, and 10 4-h periods after administration of magnesium sulphate. The maximum difference in systolic arterial pressures over each 4-h period is also shown. *The first episode of autonomic hyper-reflexia recorded during this 4-h period
 
The plasma magnesium concentration 12 h before administration of the bolus dose of magnesium sulphate was 0.6 mmol litre–1 (normal range 0.7–1.2 mmol litre–1). The plasma magnesium concentration was assayed again at 12, 24, 48, 60, and 84 h after the infusion was commenced and peaked at 5.15 mmol litre–1, 48 h after the infusion was initiated (Table 2). As this was higher than the target plasma concentration (2–4 mmol litre–1), the magnesium infusion was discontinued.


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Table 2 The plasma magnesium concentration and the infusion rates of magnesium sulphate from 12 h prior to magnesium being commenced, to 84 h after initiation of therapy. The corresponding serum creatinine levels are also shown
 
There were no apparent adverse cardiac effects associated with the high plasma magnesium concentration. Initially, there was no significant decrease in minute ventilation, with the patient maintaining normocarbia at 4.9 kPa (normal range 4.8–5.9 kPa) with volume-controlled synchronized intermittent mandatory ventilation with pressure support. (SIMV rate of 12 breaths min–1 and pressure support of 14 cm H2O above 5 cm H2O PEEP.) However, between 24 and 36 h after the infusion was commenced, the minute ventilation decreased slightly with a corresponding rise in arterial carbon dioxide tension. The respiratory rate, however, remained unaltered (Table 3). This was, therefore, attributed to a decrease in tidal volume. There was no other impairment of gas exchange. At 36 h after commencement of the magnesium infusion, the pressure support was increased to 18 cm H2O to maintain normocarbia and prevent respiratory acidosis.


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Table 3 The mean (SD) minute ventilation, arterial carbon dioxide tension (PaCO2), and respiratory rate (RR) in the 12 h period before, and in the first three 12 h periods subsequent to the magnesium infusion being commenced
 
Within 12 h of initiation of the magnesium infusion, no further episodes of autonomic hyper-reflexia were noted, in spite of the ongoing diarrhoeal illness. The level of sedation was decreased as the arterial pressure stabilized, although insulin requirements remained high at 8 units h–1. The patient subsequently made an uneventful recovery and was discharged to the ward after 11 days of intensive care.


    Discussion
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
The number of patients with chronic spinal cord injury presenting both to specialist and non-specialist units with medical conditions and for elective surgery is increasing.2 The management of conditions occurring secondary to spinal cord injury, such as respiratory failure or sepsis from the urinary tract, respiratory tract or skin, can necessitate intervention on intensive care. Of particular concern to the intensivist is autonomic hyper-reflexia, a common and potentially life-threatening condition associated with chronic spinal cord lesions. It is characterized by an uninhibited sympathetic response producing headache, flushing, and diaphoresis above the level of the lesion, together with pallor and piloerection in the lower trunk. Reflex bradycardia often accompanies the hypertension, which may be severe and prolonged. Some or all of these features may be present. Autonomic hyper-reflexia can complicate both complete and partial lesions of the spinal cord and its prevalence varies with the height of the lesion, being more common in higher spinal cord injury. It has been described in lesions above T10,3 and has a prevalence of 60–80% in lesions above T6.4 5 The onset of autonomic hyper-reflexia most commonly occurs in the reflexic stage of the condition, usually between 3 weeks and 12 yr after injury, but recent case reports indicate an earlier onset (within 7 days) in some patients during the flaccid phase.6 7 The complications of autonomic hyper-reflexia, which include myocardial ischaemia, cerebral haemorrhage, coma, and death, are attributable to the hypertensive crises, which follow uncontrolled paroxysms of sympathetic activity. It is of interest that our patient had a history of headaches associated with autonomic hyper-reflexia for which he used nitroglycerine sublingual spray. Such a history in a patient with chronic spinal cord injury should alert the intensivist to the likelihood of the patient developing autonomic hyper-reflexia when acutely ill.

Autonomic hyper-reflexia can be stimulated either by visceral or, less commonly, cutaneous stimuli below the level of the lesion. Patients with high spinal cord injury on intensive care units may be exposed to such stimuli. These include catheterization and distension of the urinary bladder, urinary tract infections, enemata, sigmoidoscopy, various causes of gastrointestinal distension, and manipulation of pressure sores.7

The pathophysiology of autonomic hyper-reflexia involves the loss of higher centre inhibition of sympathetic outflow. More importantly, however, it results from disorganized connections between pre-synaptic afferent terminal buttons (which multiply chaotically after cord injury) and interneurones within the spinal cord, which in turn synapse with sympathetic efferents.2 Patients with chronic injury to the spinal cord are also known to have decreased levels of circulating catecholamines and an increased sensitivity to norepinephrine.7 In addition, plasma norepinephrine levels rise markedly during episodes of autonomic hyper-reflexia.7

The management of autonomic hyper-reflexia requires removal of the precipitating stimulus when possible, and if necessary pharmacological intervention. In the intensive care unit it may not be possible easily to avoid, remove, or treat the precipitating stimulus, and pharmacological intervention then becomes necessary to prevent and treat life-threatening complications. Drug therapies include alpha-1 adrenoceptor blockers, beta-adrenoceptor blockers, calcium channel antagonists, alpha-2 adrenoceptor agonists, ganglion blockers, nitrates, hydralazine, and reserpine.2 6 7 8 Many of these drugs and also magnesium sulphate have played a part in the management of the paroxysms of systemic hypertension associated with tetanus and phaeochromocytoma.1 9 10

Magnesium controls catecholamine-induced hypertensive crises through several anti-adrenergic mechanisms of which calcium antagonism is of primary importance.11 Magnesium is an essential regulator of calcium movement in and out of the cell, and of the actions of calcium within the cell.12 In addition, magnesium competes with calcium for transmembrane channels. By these mechanisms, magnesium inhibits catecholamine release both from the adrenal medulla and from adrenergic nerve endings. Magnesium causes a reduction of systemic vascular resistance by a direct vasodilator effect on vessel walls and by direct blockade of catecholamine receptors.12 Magnesium possesses anti-arrhythmic properties, and offers protection from catecholamine-induced myocarditis by the preservation of intracellular adenosine triphosphate and glycogen stores and by reducing lactate production.1 9 1113 The serum concentration required to exert these effects is in the range of 2–4 mmol litre–1.1

Although magnesium has a high therapeutic index, at plasma levels above 2.5 mmol litre–1, it causes muscle weakness by the dose-dependent inhibition of acetylcholine release in peripheral nerves. Loss of tendon reflexes occurs at a plasma concentration above 5 mmol litre–1 and respiratory depression above 7 mmol litre–1.11 Muscle weakness from magnesium administration is thought to develop more rapidly if commenced in the presence of sedation.14 Small but significant reductions in pulmonary function have been reported in pre-eclamptic patients in labour receiving magnesium sulphate infusions, with plasma concentrations in the therapeutic range.15 Respiratory insufficiency is a common consequence of spinal cord injury and results mainly from muscle weakness, although there is some data to suggest that reductions in respiratory drive and ventilatory response to hypercapnia also occur.2 We therefore emphasize the ready availability of ventilatory support when administering large doses of magnesium sulphate to patients with high spinal cord injury.

Our patient was receiving ventilatory support and sedation throughout the administration of magnesium, and a decrease in minute ventilation only became apparent as the plasma level of magnesium approached the upper limit of the targeted range. The rapid rate of change of magnesium concentration was, however, probably due to the patient’s renal dysfunction. Frequent monitoring of plasma levels of magnesium is essential especially in the presence of renal dysfunction, and in view of the fact that clinical assessment of muscle weakness may prove impossible in sedated patients and in patients with chronic spinal cord injury.

In a recent case report, Maehama, Izena and Kanazawa describe the successful use of magnesium sulphate in the management of autonomic hyper-reflexia occurring during labour in a patient with high spinal cord injury.16 Our case report highlights this serious complication of spinal cord injury in the intensive care setting and introduces the use of magnesium sulphate for its management. In view of its pharmacological mode of action, its wide therapeutic index in the ventilated patient, and its successful use in the management of other systemic hypertensive crises mediated by the autonomic nervous system, we advocate further research into the use of magnesium sulphate in the treatment or prevention of autonomic hyper-reflexia secondary to chronic spinal cord injury in the intensive care unit.


    References
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 James MFM. Use of magnesium sulphate in the anaesthetic management of phaeochromocytoma: a review of 17 anaesthetics. Br J Anaesth 1989; 62: 616–23[Abstract]

2 Hambly PR, Martin B. Anaesthesia for chronic spinal cord lesions. Anaesthesia 1998; 53: 273–89[ISI][Medline]

3 Gimorsky ML, Ojeda A, Ozaki R, Zerne S. Management of autonomic hyperreflexia associated with a low thoracic spinal cord lesion. Am J Obstet Gynecol 1985; 153: 223–4[Medline]

4 Lindan R, Joiner E, Freehafer AA, Hazel C. Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury. Paraplegia 1980; 18: 285–92[ISI][Medline]

5 Amzallag M. Autonomic hyperreflexia. Int Anesthesiol Clin 1993; 31: 87–102

6 Silver JR. Early autonomic dysreflexia. Spinal Cord 2000; 38: 229–33[ISI][Medline]

7 Colachis S. Autonomic hyperreflexia with spinal cord injury. J Am Paraplegia Soc 1992; 15: 171–86[Medline]

8 Comar AE, Ibrahim E. Autonomic hyperreflexia/dysreflexia. J Spinal Cord Med 1997; 20: 345–54[Medline]

9 James MFM, Mason EDM. The use of magnesium sulphate infusions in the management of very severe tetanus. Intensive Care Med 1985; 11: 5–12[ISI][Medline]

10 Lipman J, James MFM, Erskine J, Plit ML, Eidelman J, Esser ID. Autonomic dysfunction in severe tetanus: magnesium sulfate as an adjunct to deep sedation. Crit Care Med 1987; 15: 987–8[ISI][Medline]

11 Fawcett. JW, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br J Anaesth 1999; 83: 302–20[Abstract/Free Full Text]

12 James MFM. Clinical use of magnesium infusions in anaesthesia. Anesth Analg 1992; 74: 129–36[ISI][Medline]

13 O’Riordan JA. Pheochromocytomas and anesthesia. Int Anesthesiol Clin 1997; 35: 99–127

14 Attygale D, Rodrigo N. Magnesium sulphate for the control of spasms in severe tetanus. Anaesthesia 1999; 54: 297–310

15 Ramanathan J, Sibai BM, Duggirala V, Maduska AL. Pulmonary function in preeclamptic women receiving MgSO4. J Reprod Med 1988; 33: 432–5[ISI][Medline]

16 Maehama T, Izena H, Kanazawa K. Management of autonomic hyperreflexia with magnesium sulfate during labor in a woman with spinal cord injury. Am J Obstet Gynecol 2000; 183: 492–3[ISI][Medline]





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