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Abstract

Nerve injury is a common complication following intramuscular injection and the sciatic nerve is the most frequently affected nerve, especially in children, the elderly and underweight patients. The neurological presentation may range from minor transient pain to severe sensory disturbance and motor loss with poor recovery. Management of nerve injection injury includes drug treatment of pain, physiotherapy, use of assistive devices and surgical exploration. Early recognition of nerve injection injury and appropriate management are crucial in order to reduce neurological deficit and to maximize recovery. Sciatic nerve injection injury is a preventable event. Total avoidance of intramuscular injection is recommended if other administration routes can be used. If the injection has to be administered into the gluteal muscle, the ventrogluteal region (gluteal triangle) has a more favourable safety profile than the dorsogluteal region (the upper outer quadrant of the buttock).

Keywords

Gluteal injection intramuscular injection nerve injection injury sciatic nerve

Introduction

The World Health Organization has estimated that of the ∼12 billion injections administered globally every year, 50% of them are unsafely administered and 75% are unnecessarily administered.¹ Nerve injection injury (NII) is a common complication following intramuscular injection and the sciatic nerve is the most frequently affected nerve.^2,3 Sciatic nerve injection injury (SNII) has been recognized for many years: ‘sciatic neuritis due to injection’ was first reported in 1882⁴ and sciatic nerve injuries were reported after quinine injections as early as 1920.⁵ However, SNII remains a persistent global problem that affects patients in both wealthy and poorer healthcare systems.⁶

The sciatic nerve is formed from the anterior and posterior divisions of the L4, L5, S1 and S2 spinal nerves and the anterior division of the S3 spinal nerve. The anterior divisions form the tibial division of the sciatic nerve, while the posterior divisions form the peroneal division. The two divisions usually run together in the pelvis and then pass beneath the piriformis muscle, with the peroneal division lying lateral to the tibial division.⁷

The pathology of injection injuries varies depending on the injection site and the agent injected. Extrafascicular injection produces no or minimal nerve injury. In contrast, intrafascicular injection results in nerve damage ranging from minimal to severe, depending on the agent used and the dosage.⁸ Pathological alterations following intrafascicular injection include both gross and microscopic changes. After injection of neurotoxic agents, the nerve appears pale and swollen, often with petechial haemorrhages or grey discoloration.⁹ On microscopic examination, toxic effects can be seen in both the axon and the Schwann cell with its myelin sheath. Histologically there are axonal changes, with splitting and fragmentation of myelin and axon, condensation of axoplasm, swelling of mitochondria with disruption of the cristae or complete delamination of the myelin sheath.⁹ Schwann cells also show damage, with clumping and condensation of both nuclear and cytoplasmic material, or loss of the nuclear membrane with dissolution of the nucleoplasm.⁹ With time, further axonal degeneration and myelin breakdown are seen with Wallerian degeneration.¹⁰ Connective tissue proliferation and scar formation also occur. Early signs of axonal regeneration with reduplicating Schwann cells and axonal sprouting can be seen 1–2 weeks after nerve injury, and further regeneration is usually well advanced by 2 months.¹⁰

The occurrence of SNII may induce minor transient pain without neurological sequelae, or can present with severe sensory disturbance and motor loss with poor recovery (and be associated with medicolegal claims). The present article reviews this serious complication, including its mechanism, clinical course, management and prevention. A PubMed® database search was performed, including dates between 1920 and 2012 using the search terms ‘sciatic nerve’, ‘sciatic nerve injury’, ‘sciatic neuropathy’, ‘injection injury’, ‘intragluteal injection’, ‘intramuscular injection’, together with anatomical structures relevant to this review, including ‘peripheral nerve’ and ‘piriformis muscle’.

Reporting and incidence

Nerve injection injuries are fairly common although less frequently reported, so their overall incidence is unknown. These injuries are probably under-reported because the condition has become so well known to physicians that descriptions of these cases are considered unnecessary for publication.

The sciatic nerve is the most commonly involved nerve. Kline et al.² reported that injection was the most common injury mechanism affecting the sciatic nerve at the buttock level, accounting for more than half of the cases (136/230 patients) in their 24-year study. The incidence of this complication seems to be higher in economically poorer countries due to intramuscular injections being administered by inadequately trained or unqualified staff.^3,11,12 Tak et al.³ reported that 89.7% (278/310 patients) of patients with NII in the Kashmir region of India had sciatic nerve injury; the injections had been administered by unqualified personnel in 83% of the cohort (258 patients). In Pakistan, the estimated annual incidence of traumatic injection neuropathy (over 90% of which involved the sciatic nerve) was 7.1 per 1 million children under 3 years old receiving polio vaccination.¹¹ Many of these cases occurred in rural areas and involved the children of unskilled parents, suggesting limited access to (and affordability of) qualified medical practitioners.¹¹

Villarejo and Pascual¹³ reported 370 cases of SNII in children <10 years of age over a 20-period, ∼50% of which occurred in infants <1 year of age. Younger age groups may be particularly at risk of SNII due to their smaller gluteal covering and gluteal mass volume to sciatic nerve size ratio. Patients who are thin as a result of age and/or debilitating disease also have a predisposition to SNII because they have a smaller amount of gluteal soft-tissue covering, compared with other people.^2,14

Injection injury is the second most-common cause of sciatic neuropathy after hip arthroplasty.¹⁵ Sciatic nerve palsy has also been reported after catheterization of umbilical vessels.¹⁶

Mishra and Stringer⁶ reviewed published medicolegal reports of sciatic nerve injuries published between 1989 and 2009 in North America. They identified nine court decisions in favour of the plaintiff. The total compensation was <US$4 000 000. Another study searched legal databases in Canada and the USA between 1970 and 2003; of the 16 court decisions identified, six were decided in favour of the plaintiff, and the courts judged that intramuscular injections could cause SNII.¹⁷

Mechanisms of injury

Direct needle trauma

The injection site chosen and administration technique used are important determinants of injury.^2,3,14,17 The sciatic nerve is located in the middle of the gluteal region and usually passes deep to the piriformis muscle. Injections administered outside of the upper outer quadrant of the buttock (the dorsogluteal region) are a major cause of SNII, with the sciatic nerve being more prone to damage when the site of injection is more medial and/or inferior. The peroneal division of the sciatic nerve is more frequently injured than the tibial division because of its more lateral position, reduced protective connective tissues, and the relative tethering of the nerve course.^2,13,18 Anatomical variations, such as an absence of (or abnormal subdivision of) the piriformis muscle, or the passing of the peroneal division through the piriformis muscle, may also be associated with nerve injuries after injection.^19,20

The length of the needle, the angle of the needle and the position of the patient during injection (such as lateral decubitus, upright or leaning forward instead of prone) are other major factors in NII.^14,17,21 Inappropriate injection methods, such as when restraining an agitated child, may also result in injection injury.²² The type of needle seems to influence nerve penetration. Hirasawa et al.²³ studied the effect of different types of needles on the degree of SNII during nerve blockade in rabbits. They reported that a tapered injection needle did not cause any damage or tearing of the nerve fibres and resulted in the lowest level of damage to the perineurium. With both short- and long-bevelled needles, neural damage was reduced when the face of the bevel was inserted parallel to the nerve fibres. Severe neurological dysfunction has been seen in animal models, after intraneural injections.²⁴

In developing countries, many cases of NII can be attributed to unregistered medical practitioners who use inappropriate injection techniques.^3,12,25 In such countries, the parents of sick children may put pressure on medical practitioners, urging them to administer injections because the parents mistakenly believe that injections will help heal their children quicker than other forms of treatment.³

Ischaemia

Ischaemia is one of the main pathological mechanisms of SNII. Drug injection may cause scar formation, leading to the development of fibrosis, which constricts nerve bundles and surrounding tissues (and limits blood flow).²⁰ Neural ischaemia may also arise from an increase in intraneural pressure, causing temporary interruption of blood flow. In an animal study, all injections associated with low intraneural pressure produced only transient motor dysfunction, whereas high injection pressures were associated with persistent motor deficits, destruction of neural architecture and degeneration of axons.²⁴ Neural ischaemia is more severe if a vasoconstrictor is added to the drug; Selander et al.⁸ performed intrafascicular injections of bupivacaine on the rabbit sciatic nerve, and reported that more axonal degeneration was seen when adrenaline was added, compared with bupivacaine alone.

Agents associated with SNII

The nature of the injection agent is another important factor, with the degree of nerve damage depending on the type and amount of drug administered.^8,10 In an animal study, normal saline produced only intraneural oedema, even when injected into the nerve fascicle. In contrast, a neurotoxic agent (such as ropivacaine) caused nerve injury both when injected into and when extraneurally placed onto a nerve, with marked histological abnormalities including oedema, axonal destruction and Wallerian degeneration.²⁶ Nerve damage has been reported to increase with increasing concentrations of the drug administered.⁸ For obvious reasons, intrafascicular injections can cause more damage to the nerve than extrafascicular or extraneural injections.^19,26

A breakdown in the blood–nerve barrier following nerve injury is well recognized.^8,9 Intrafascicular injection of neurotoxic agents into the rat sciatic nerve produced a marked increase in the permeability of the perineurium and endoneurial capillaries within 30 min after injection.⁹

A number of agents have been associated with SNII, including analgesics (diclofenac,⁶ tramadol,⁶ metamizole¹²), antiemetics (meperidine with hydroxyzine²), antibiotics (penicillin,²⁷ gentamicin,¹⁰ chloramphenicol,¹⁰ benzathine–procaine benzylpenicillin mixture,²⁸ cefuroxime²⁰), antimalarials (quinine,⁵ chloroquine,¹² sulphadoxine–pyrimethamine¹²), vitamin K,²⁰ local anaesthetics (lidocaine,²⁹ procaine,²⁹ ropivacaine²⁶), vaccines,² steroids,² phenobarbital²⁰ and paraldehyde.¹²

Penicillin administered into the sciatic nerve of dogs has been shown to result in granuloma formation.²⁷ Lidocaine, procaine and tetracaine split the myelin lamellae and caused more severe damage than bupivacaine.²⁹ Ropivacaine administered intraneurally into the sciatic nerve of rats caused severe demyelination and Wallerian degeneration.²⁶ Senes et al.²⁰ evaluated the neurotoxicity of several agents; hydroxybenzoate, alcohol and glycerol diacetate were found to be the most neurotoxic, with cefuroxime sodium and phenobarbital being moderately neurotoxic. Naloxone with hydroxybenzoate, vitamin K with glycocholic acid and lecithin, and glycocholic acid and lecithin used alone were the least neurotoxic, but still caused nerve injuries.²⁰ Gentili et al.¹⁰ reported a moderate degree of nerve-fibre damage after intrafascicular injections of chloramphenicol, gentamicin, iron dextran and cephalothin in rats, with more damage being seen in large fibres. Extrafascicular injections did not always produce nerve damage. However, highly neurotoxic agents (such as benzylpenicillin, diazepam and chlorpromazine) produced a degree of nerve injury, even when injected extrafascicularly.¹⁰ Yaffe et al.³⁰ evaluated 11 different agents in rats and found that benzylpenicillin, diazepam and chlorpromazine were the most neurotoxic.

SNII presentation

Nearly 90% of patients with SNII have an immediate onset of symptoms; 10% of patients have a delayed onset that appears minutes to hours after the injection.^7,14 This difference could result from the locus of the injection. Intraneural injection appears to cause an immediate onset of symptoms, whereas delayed onset may be related to placement of the injection, either close to the nerve or into the epineurium, with central diffusion leading to damage to the fascicles, over time.^2,13,14

Patients with sciatic nerve injury present with pain, paraesthesia and causalgia along the nerve distribution. Pain is present in the majority of cases and may be described as a severe shooting or burning sensation.^2,13,14 Motor function may be more severely impaired than neurosensory function.³¹ Since the peroneal division is frequently involved, paralytic foot drop is a common presentation due to a deficit of dorsiflexion and eversion.^2,6,13,20 Involvement of the tibial division may lead to loss of plantar flexion of the foot, loss of flexion of the toes and weakened inversion of the foot. Some patients may suffer a complete sciatic nerve lesion proximal to the hamstring, with a sciatic distribution of pain and paraesthesia, impaired knee flexion, a flail foot due to loss of dorsiflexion and plantar flexion, a loss of posterior tibialis foot invertors and peroneus longus and brevis foot evertors, and sensory loss to the posterior thigh, lower lateral leg and foot. This degree of injury may lead to pressure sores, infections, claw toes and even limb amputation.⁷ Delayed vasomotor changes may be present in the involved limb, with cold sensation, erythema, skin thinning and oedema.³² In children, the affected side may show decreased foot growth and leg-length deformities later in life.²⁰

Obach et al.³³ described four types of paralysis resulting from intragluteal injection: immediate neurogenic involvement with instant pain; obvious paralysis without pain (the most frequent type); subacute or late paralysis without immediate pain; late paralysis with immediate pain. They reported that there was immediate paralysis in 91% of all SNII, presumably due to intraneural injection of the drug. The late onset of paralysis was explained by injection around the nerve, toxic swelling, vascular lesions and necrosis.³³

SNII diagnosis

Clinical examination, magnetic resonance imaging and electromyography are used in the diagnosis of SNII. Magnetic resonance neurography shows increased signal intensity on T2-weighted images of injured nerves and can also help in the detection of postinjury neuroma formation.^34,35 Electromyography can be conducted on the extensor digitorum brevis, tibialis anterior, medial head of the gastrocnemius and the short head of the biceps femoris muscles using a concentric needle electrode.²⁵ It may show signs of acute denervation, presenting as a high insertional activity, positive spontaneous fibrillation, and sharp waves with low interference and recruitment in the affected muscles; alternatively it may show signs of chronic denervation with reinnervation, presenting with polyphasia, high amplitude, and a lowered interference pattern and recruitment in the affected muscles.^36,37

Compound muscle action potential amplitude, sensory nerve action potential amplitude and nerve conduction velocity can also be used in the diagnosis of SNII.³⁶ A motor nerve conduction study can be performed on the common peroneal and posterior tibial nerves, with electrodes placed on the extensor digitorum brevis and abductor hallucis longus muscles, respectively. A sensory nerve conduction study of the sural and superficial peroneal nerves can be performed, with averaging of the sensory nerve action potential.²⁵ The relative involvement of peroneal and tibial lesions could be determined by comparing the muscle strength of the affected muscles and the electrophysiological findings.^25,36 For example, no or minimal response from the peroneal division and a minimal or moderate response from the tibial division on electromyography will be seen when the peroneal division is more affected than the tibial division.³⁸

Foot drop caused by peroneal injury may be misdiagnosed as congenital clubfoot in infants, leading to a delay in the diagnosis of SNII. Cavovarus and calcaneovarus foot deformities in children have been reported as resulting from SNII.³⁹ Napiontek and Ruszkowski⁴⁰ reported that children with an equinus or equinovarus deformity were diagnosed on average 3.8 months after the gluteal injection had been performed, but gluteal fibrosis was not diagnosed until 5.1 years after the injection. For obvious reasons, pain and neurosensory loss may be difficult to evaluate in neonates and infants, therefore, SNII diagnosis should primarily focus on motor loss in these very young patients.²⁰

NII management

Treatment of NII should be individualized for each patient depending on the clinical history, clinical examination and the results of investigations such as electromyography, magnetic resonance neurography or nerve conduction studies. Sunderland⁴¹ classified NII and its treatment as follows: for first-degree NII (reversible conduction block), conservative management is sufficient; for second-degree NII (Wallerian degeneration with reactive fibrosis, slow recovery, often incomplete), neurolysis is indicated; for third-degree NII (necrosis and fibrosis due to neurotoxicity of the agent, no spontaneous recovery), flushing is indicated to limit the toxicity, but the drug has often already been completely reabsorbed at the time of surgery.

If the patient complains of numbness, paraesthesia, pain or other symptoms of SNII, immediate flooding of the subgluteal space with a physiological solution may dilute the agent and prevent nerve injury.⁴² Analgesics and other drugs for pain control (such as tricyclic antidepressants and gabapentin) may be required.^2,43 Keskinbora and Aydinli⁴³ reported that neuropathic pain due to SNII in a child was completely controlled by gabapentin at a dose of 400 mg, three times daily. Physiotherapy is also indicated to prevent atonia in patients with pain syndromes who do not have functionally incapacitating or severe motor loss.¹³ For patients with foot drop, early use of a dorsiflexion splint or articulated brace may encourage proper ambulation.²

Surgical exploration is recommended for an incapacitating or complete deficit of the tibial or peroneal distributions without signs of clinical or electromyographical recovery within 3–6 months.^2,13 Senes et al.²⁰ recommended that surgery should be performed within 4 months of the injury. Villarejo and Pascual¹³ reported that excellent results were achieved when patients underwent surgery between 3 and 6 months after injury. However, Topuz et al.⁴⁴ proposed that surgical exploration should be performed without waiting for electrophysiological substantiation if nerve transection is suspected; early surgical intervention may have a better prognosis than late intervention, because there is less time for fibrosis to develop.

After a diagnosis of NII, waiting for 3–6 months before surgical exploration (with nerve action potential recording) is generally recommended if the injury is not severely incapacitating and the pain is minimal.^2,13 If an action potential is present beyond the lesion, external neurolysis alone or with internal neurolysis is indicated. If there is no action potential beyond the lesion, suture or graft repair is required.^14,20,42

Defining the extent of injury in the nerve on the operating table may be challenging. A nerve injury induces fibre thickening, and a neuroma-in-continuity with a yellowish aspect and hourglass deformity or bulky appearance may be seen.²⁰ The wide spectrum of pathological changes that may be seen in an injured nerve during resection was reported by Gilles and Matson:⁴² during resection of the peroneal and tibial branches of the sciatic nerve, cicatrix formation, multinucleate giant cells, crystalline deposition, abnormal circumferential collateral growth of axons, replacement of myelinated axons with collagen, dense scarring and fibrotic changes were observed in different patients. One patient had a low number of distal axons, macrophages throughout, and more damaged central axons than peripheral axons. The damaged nerve may appear opaque to transmitted light and a transillumination test can be used to determine the exact limit of resection.

Follow-up monitoring of nerve regeneration is important. The detailed pathomorphological visualization of nerve injury provided by magnetic resonance neurography has the potential to detect excessive epi- or intraneural scar or true neuroma formation, ﬁndings that are likely to correlate closely with insufficient spontaneous recovery, thereby guiding the decision to perform surgical nerve repair.¹⁸ The return to normal of T2-weighted images showing hyperintense signals in an injured nerve has been correlated with nerve regeneration and its clinical manifestations.^18,34

Diffusion tensor tractography, a type of magnetic resonance imaging, has also been used to monitor the state of regenerating neurons. The fractional anisotropy value decreases after nerve injury and correlates with the total number of regenerating axons, and therefore indicates functional improvement.⁴⁵

In children, if incomplete motor recovery results, a dynamic elastic splint may be applied initially. During growth, orthopaedic surgery (such as musculotendinous transposition or femoral lengthening) may be needed to correct the palsied foot or limb length discrepancy.²⁰

The prognosis of patients with NII depends on the nerve division involved, the level of injury, the timing of repair and the patient’s overall health status. Neurolysis and nerve graft repair have a better prognosis when performed on the tibial division of the sciatic nerve than on the peroneal division;^7,14 this may be due to the improved blood supply to the tibial division. The presence of nerve action potentials and early functional recovery are also positive prognostic factors.^14,46 Most poor results occur in chronic cases with no motor function on neurological examination and absent efferent potentials on electromyography.¹³

Most patients who do not require surgical exploration achieve good results. Spontaneous recovery to a useful level was seen in 84% of injuries to the tibial division and 68% of injuries to the peroneal division, in medically managed patients.² Surgical outcomes are diverse and depend on the procedure performed. In a review by Yeremeyeva et al.,¹⁴ neurolysis improved functional outcomes in 84% and 68% of tibial and peroneal division injuries, respectively. Acceptable functional outcome was achieved in in 75% and 33% of tibial and peroneal division injuries, respectively, after suture repair, and in 57% and 25% of such injuries, respectively, after grafting. Villarejo and Pascual¹³ reviewed cases of children with motor weakness, and found that all children with peroneal or tibial injury attained good results regardless of whether surgical or physical therapy was used, while good results were achieved in 50% of children with paralysis of the sciatic nerve trunk (both the peroneal and tibial components).

A number of agents have been shown to improve nerve regeneration in animal models and may have potential for the clinical management of NII in the future. For example, treatment with local plasmid human vascular endothelial growth factor-165 has been shown to have beneficial effects on the regeneration of nerves and acceleration of recovery of the injured sciatic nerve in rats.⁴⁷ Nerve growth factor and glial cell line-derived neurotrophic factor have been reported to promote nerve regeneration, significantly increasing the density of axons and promoting nerve recovery in rats.^48,49 Acetyl-l-carnitine also considerably improved nerve regeneration in rats.⁵⁰ Tacrolimus (FK506) was reported to increase the number of regenerated neurons and axons, and transforming growth factor-β reactivated Schwann cells and increased their capacity to support axonal regeneration in a rat model.⁵¹

NII prevention

Total avoidance of intramuscular injection is recommended if other routes of administration can be used; intramuscular injections can be replaced with intravenous injections or suppositories in children.^12,25 If there is no alternative to intramuscular injection, the gluteal region, especially in children aged < 5 years, should be avoided to prevent SNII; other intramuscular injection sites that may be used include the anterolateral thigh and deltoid regions.^6,52

Administration of intramuscular injections involves attention to the appropriate site of needle insertion, needle size and angle of injection.⁵² If the injection is administered into the gluteal region, use of the whole dorsogluteal region (commonly known as the upper outer quadrant of the buttock) lacks precision; the injection is less likely to result in injury if administered in the ventrogluteal region (gluteal triangle), which is the lateral and superior part of the dorsogluteal region and can be formed by placing the palm of the opposing hand on the greater trochanter, pointing the index finger to the anterior superior iliac spine and pointing the middle finger toward the iliac crest.⁶ The needle should be inserted at an angle of 90° to the skin in this triangle. The subcutaneous fat is thinner at the ventrogluteal site and hydrophilic chemicals can therefore be well absorbed; the muscle is also thicker at this site.⁶ Some physicians also suggest that intragluteal injections should be administered superolateral to a line joining the posterior superior iliac spine and greater trochanter.⁵² However, paralysis of the tensor fascia latae muscles has been reported after ventrogluteal site injection.⁵³ Therefore, no method of gluteal injection can be guaranteed not to cause nerve injury.

Use of an optimal injection volume may also be important. It may be necessary to split the dose to avoid pain, allow appropriate absorption and avoid trauma. The amount of agent that can be injected into the gluteal mass varies between 3 and 5 ml.⁵³

Conclusions

Sciatic nerve injury is a preventable complication of intramuscular gluteal injection. Total avoidance of such injections is desirable, but if a gluteal injection is essential, use of an appropriate administrative technique is crucial. If any NII is suspected, immediate and optimal injury management can reduce neurological sequelae and maximize the likelihood of recovery.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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