Case Report

acute paraplegia and pulmonary edema after benzathine penicillin injection

Abstract

Accidental intra-arterial injection is a potentially devastating complication of the intragluteal injection of benzathine penicillin. A 35-year-old woman developed after Intramuscular injection of benzathine Penicillin G acute paraplegia and Noncardiogenic pulmonary edema. Noninvasive positive pres- sure ventilation was initiated with furosemide and corticoster- oids. A magnetic resonance imaging scan showed findings consistent with syringomyelia and spinal cord ischemia at T9 through T10. Vascular injury may be the result of microemboli of the injected crystals of the penicillin salts. The mechanism of noncardiogenic pulmonary edema is perhaps an immunogically mediated one. At 2-year follow-up, she had no improvement in neurologic status. The deficit is considered permanent.

Intramuscular injection of benzathine penicillin G is frequently widespread in Developing countries to prevent the occurrence of acute rheumatism fever [1]. If anaphylactic complications are well known, another related to inadvertent intravascular administration has been documented to cause severe injuries such as Nicolau syndrome (lipoatrophy), transverse myelitis, injury to sciatic nerve as well as Hoigne syndrome (transient central nervous system dysfunction) [2-7]. The advanced mechanism of injury is the migration of emboli in arterial circulation.

We reported a case of a paraplegia that was a result of an inadvertent intra-arterial injection of benzathine penicillin G associated with an noncardiogenic acute pulmonary edema wherein the proposed mechanisms are discussed.

A 32-year-old woman with a medical history of streptococcal pharyngitis since childhood presented to the emergency department (ED) twice over a period of a few days complaining of streptococcal pharyngitis. She had been seen by her primary care physician 72 hours before her first ED visit and was given an intramuscular injection of benzathine penicillin G. She did not have cardiac or respiratory disease. The injection was done in the upper outer quadrant of the left buttock. No blood return was noted when the syringe was aspirated before the injection. Immediately after the injection, the patient complained of an Intense pain and developed

paraplegia, respiratory distress, and hemoptysis, requiring transfer to the intensive care unit.

Findings on physical examination at admission in the intensive care unit were as follows: heart rate of l65 beats per minute, blood pressure of 120/70 mm Hg, temperature of 38?5, Glasgow Coma Scale score of 15. Respiration was shallow and was at a rate of 38/min, and oxygen saturation decreased to 80%. Chest auscultation revealed bilateral coarse crepitations suggestive of acute pulmonary edema. Cardiac examination revealed tachycardia without any heart sound. Neurologic examination revealed a sensory level at T10 with a flaccid paraplegia and abolition of the deep tendon reflexes in both lower extremities. The anal reflex was absent. Complete blood picture showed increased white blood cell count at 23 x 10⁹/mL without hypereosinophilia, and C- reactive protein increased to 72 mg/L. The initial blood gas analysis showed the following values: PaO2/fraction of inspired oxygen, 180; PaCO2, 30 mm Hg; pH, 7.45. There was no significant data value in other laboratory tests. Her chest radiograph showed bilateral perihilar infiltrates consistent with pulmonary edema (Fig. 1). Electrocardiogram showed a

sinusal tachycardia.

An echocardiogram showed moderately pulmonary arterial systolic pressure (50 mm Hg), a septal hypokinesia, and a normal left ventricular systolic function with an

Fig. 1 The chest x-ray revealed pulmonary edema.

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ejection fraction of 69%. A diagnosis of Noncardiogenic acute pulmonary edema was made, and the patient was given furosemide 60 mg every 6 hours and methylprednisolone

120 mg every 6 hours. noninvasive positive pressure ventilation was initiated with a fraction of inspired oxygen of 0.6, a positive end-expiratory pressure of 10 cm H₂O, and a pressure support level of 15 cm H₂O.

A magnetic resonance imaging (MRI) scan of the thoracolumbar spine was done 72 hours after the onset of symptoms. The MRI showed a dorsal syringomyelic syrinx with evidence of cord edema (Figs. 2-4). Results of a lumbar puncture were normal. An echocardiogram obtained

Fig. 2 Dorsolumbar MRI (sagittal T2-weighted image) showing hyperintense signal from T7 through T9 suggestive of syringo- myelia syrinx (arrow).

Fig. 3 T1-weighted transverse MRI at the T7 level shows the hyposignal, central, intramedullary lesion consistent with syringomyelia.

72 hours after the episode showed normal cardiac function. On the seventh day, a follow-up MRI scan was obtained, which showed findings consistent with spinal cord ischemia at T9 through T10.

Immunoglobulin (Ig) A, IgM, IgE, anti-DNA antibodies, lupus anticoagulants, anticardiolipin antibodies, and lupus erythematous cells were all normal. There was an increase in the hemolytic complement IgG, C3, and C5 value. Electro- myography revealed pronounced denervation activity and markedly slow nerve conduction velocity with evidence of conduction block. However, we noted the daily recurrence of a subacute pulmonary edema at approximately the same hour, requiring the recourse to noninvasive positive pressure ventila- tion. She recovered from hypoxemia, and the bilateral opacities on chest radiograph had completely resolved 14 days later.

On the l5th day of hospitalization, the episodes of the subacute pulmonary edema disappeared. The patient left the hospital on the 27th day but came back for sessions of Physical therapy. After obtaining informed consent, we performed allergologic evaluation 3 months after the incident. Serial skin prick and intradermal tests were performed on the surface of the forearm with penicillin, and results were negative.

At 3- month, 6-month, and 2-year follow-up, the patient has had no improvement in neurologic status. The deficit is considered permanent.

Despite of the very wide use of benzathine penicillin G all over the world, accidents related to accidental intra-arterial injection are rare but dramatic [7]. Indeed, they reach a younger population, with most noticed cases described in children whose ages vary between 6 and 12 years. Few cases were reported for adults [8]. This is related to the fact that the use of the benzathine penicillin G is more widespread in children. The onset of symptoms is immediate, including

paleness, intense pain around the injection site, a heat sensation at the level of the lower limbs then paraplegia [9]. In all cases described in the literature, the medication was given in the upper outer quadrant of the buttock as in the case

of our patient [4-6].

types of injuries include semicircular lipoatrophy; sciatic neuropathy; gangrene of the penis, scrotum, or perineum; gangrene of ipsilateral or controlateral feets; and transverse myelitis [2,6]. In a recent review of the nonallergic adverse reactions after benzylpenicillin injection, Miranda et al [7] reported 7 cases of paraplegia. All cases reported flaccid paralysis of the lower extremities with loss of sphincter control. The level of sensory involvement localizes the spinal cord lesions to the T10 through T11 level [4].

The lumbar puncture was not necessary because it was not very contributive to the diagnosis. On the other hand, the MRI constitutes the preferred paraclinical examination. To our knowledge, this is the first case explored with MRI. The findings are consistent with transverse myelitis.

Although the clinical syndrome of intra-arterial injections is well defined, the underlying pathophysiologic mechanism remains unclear. Many mechanisms have been proposed and all result in tissue ischemia distal to the injection site.

The first explanation is that the frequency of gluteal injuries suggest that the mechanism is inadvertent injection into branches of the superior gluteal artery located in the upper outer quadrant.

Some authors hypothesized that penicillin suspension injec- ted into the superior gluteal artery under high pressure could flow retrograde into the internal iliac artery and then to the aorta, leading to obstruction of the lumbar spinal arteries [7]. In the thoracolumbar region, all of the Blood supply to the spinal cord is derived from a single artery from the aorta, the artery of Adamkiewicz. The retrograde flow could extent further up the aorta to the level of the artery of Adamkiewicz. From that vessel, the product would pass into the anterior spinal artery and result in transverse myelitis. Obstruction of this vessel could be expected to result in a cord lesion between T9 and T12. The experiments practiced on animals showed that the obstruction of medullar vascularization on the level of the Adamkiewicz artery caused ischemic lesions. When the anterior spinal artery was ligated above the Adamkiewicz artery, the neurologic deficits were minor, whereas a ligature on top of this artery would cause

paraplegia and other neurologic deficits [10].

Others authors postulated that the drug can produce arterial vasospasm when injected to the arteries. But this mechanism is unlikely. First, the reported injuries are too distant. Second, some injuries have been duplicated in rabbits with intra-arterial but not periarterial injection [11].

Fig. 4 Saggital T1-weighted MRI of the dorsolumbar spine shows (A) a hypodense, central, intramedullary lesion from T7 through T9 consistent with syrinx and (B) enlargement of the cord suggestive of cord edema.

These results strongly suggest that tissue damage produced by penicillin is secondary to the intra-arterial administration of the drug.

However, poor collateral supply, as in the case of our patient, maximizes the potential for permanent disability in this area. Posttraumatic syringes are often found in the vascular watershed regions within the cord.

Syringomyelia is a condition consisting of a fluid cavity formed in the central canal of the spinal cord. This formation has been associated with trauma, congenital anomalies, tumors (eg, astrocytoma, hemangioblastoma, ependymoma), and arachnoiditis. The inflammatory responses of the nervous system to trauma results in edema and sometimes in cyst formation. We do not think, however, that it is posttraumatic syringomyelia. In fact, posttraumatic syringo- myelia develops between 3 months and 34 years after spinal cord injury [12].

Vascular injury may be the result of microemboli of the injected crystals of the penicillin salts. Embolization of other ingredients or Allergic reactions to them could play a role (sodium citrate, carboxymethylcellulose, polyvidone) [13].

Because the benzathine benzyl penicillin injectable suspen- sion is viscous and opaque, it would hint of the visualization of blood on aspiration ifa blood vessel were inadvertently entered.

Although some authors have suggested allergic reactions as the exact mechanism of transverse myelitis. Allergic reactions to penicillins represent the most frequent cause of immunologic drug reactions mediated by specific immuno- logic mechanisms [14,15]. Type 3 reactions are associated with autoimmune responses producing local ischemia and/or necrosis as a result of complement by IgG and IgM antibodies and complement [15]. This can be supported by the fact that the mechanism of noncardiogenic pulmonary edema in our patient is perhaps an immunogically mediated mechanism. The increased circulating immuno- complexes and complement consumption perhaps support this hypothesis.

For our patient it was initially thought that the most likely cause for the sudden pulmonary edema was Neurogenic pulmonary edema. Neurogenic pulmonary edema is gen- erally viewed as a form of noncardiogenic pulmonary edema related to massive sympathetic discharge. Neurogenic pulmonary edema is a recognized complication of a neurologic event, commonly subarachnoid bleeds and major head injuries [16]. It is thought to be related to a central sympathetic discharge as a consequence of acute hypothalamic dysfunction and medullary ischemia. Many of these patients are found to have echocardiographic evidence of reversibly reduced left ventricular systolic function without a history of heart disease.

The pathophysiologic mechanism of this adverse effect is poorly understood, although this pulmonary edema could be caused by mediator release and complement activation resulting in endothelial damage.

The recurrence of the pulmonary edema in a cyclic and daily way around the same time can be explained by the long half-life of the drug [17].

Benzathine penicillin G has an extremely low solubility; thus, the drug is slowly released from intramuscular Injection sites. The drug is hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower but much more prolonged than those of other parenteral penicillins. Intramuscular administration of 1200000 units of penicillin G benzathine in adults results in blood levels of 0.03 to 0.05 U/mL, which is maintained for 14 days.

We suggest that both mechanisms contributed to the paraplegia and to the acute edema. Moreover, considering the wide use in pediatrics, it is necessary to do good retaining of the child to avoid any immobilization during intramuscular injection. Some authors recommended that these injections be made in the upper lateral thigh in a vertical or oblique plane with a short needle [9] It is recommended to aspirate before injecting and to stop the procedure if intense pain develops.

Because of the impact of this disease on public health, the World Health Organization has helped establish programs for the prevention of recurrent attacks of rheumatic fever in many developing countries [1]. The importance of pre- ventive measures in reducing the incidence, morbidity, and mortality of this disease is undisputed. An injection of 1200000 units of this long-acting penicillin preparation every 3 weeks is justified and recommended.

The advantages of benzathine penicillin G (low costs, compliance) must be weighed against the inconvenience to the patient and pain of injection that cause some individuals to discontinue prophylaxis.

Although still rare, this disastrous complication should require particular precaution as described. For adults, physicians should be aware of the potential damage resulting from long-acting penicillin and prescribe the oral form.

Khalid Mjahed MD Sd Youssef Alaoui MD Siham Salam MD Barrou Lhoucine MD

Service d’Anesthesie-reanimation Centrale CHU Ibn Rochd Casablanca Morocco 20200 E-mail address: [email protected]

doi:10.1016/j.ajem.2007.04.013

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