Myositis, rhabdomyolysis and compartment syndrome complicating influenza A in a child

Abstract

A previously fit and healthy 8-year-old boy died following severe complications of influenza A. He developed lethargy and vomiting before presentation. On presentation to medical attention, on day 4 of his illness, he was in extremis and had extensive myositis, rhabdomyolysis, renal failure and compartment syndrome, which were resistant to supportive medical management.

Background

Compartment syndrome secondary to viral myositis is a recognised but rare complication.^1–7 Clinicians need to be alert to the more unusual symptoms of influenza infection. In the case presented here, early intervention may have prevented the progression of compartment syndrome, limited the rhabdomyolysis. and ameliorated the effects of or prevented the renal failure.^2,4,7 Earlier diagnosis may also have allowed the use of neuraminidase inhibitors.^8,9

Case presentation

A previously fit and healthy 8-year-old boy presented to his local accident and emergency department, following a 3 day history of temperature and coryzal symptoms.

His 5-year-old sibling had become unwell with similar symptoms 1 day before the patient.

Over the 3 days he became more lethargic and started vomiting 1 day before admission to intensive care. He had also found it difficult to walk, being helped to the toilet by his father on the day of presentation to the emergency department. There was no history of trauma.

While waiting to be seen in the emergency department the patient collapsed. Initially he had a low cardiac output with a heart rate around 150/min, but output was rapidly lost and cardiopulmonary resuscitation (CPR) commenced. CPR was continued for 15 min and 5 doses of epinephrine (10 μg/kg per dose) were administered as well as 50 ml/kg fluid (0.9% saline). During this time, he was also intubated and ventilated.

Upon return of spontaneous circulation, norepinephrine and epinephrine infusions were started. It was noted during the arrest that he had a low blood glucose concentration (2 mmol/l) and urine dipstix revealed no ketones. He was given a bolus of 5 ml/kg 10% dextrose. There were no further episodes of hypoglycaemia. During this time a left femoral central venous line was sited.

Intravenous cefotaxime was started and blood cultures were taken. The worst arterial blood gas during this time showed a pH 6.896, base deficit of −28 and lactate of 28 mmol/l.

The patient was transferred by the Children’s Acute Transport Service to a paediatric intensive care unit (PICU) within 12 h of presentation. Upon arrival at the PICU the patient was already intubated and ventilated and on norepinephrine and epinephrine infusions for fluid resistant hypotension. He was in multi-organ failure with lung, cardiovascular, coagulation and renal involvement.

His left femoral central venous line had been re-sited to the right groin by the transport team after they noted that the left thigh appeared swollen with cool peripheries and weak pulses from the knee down. Initial arterial blood gas showed values of pH 7.13, Pco₂ 5.56 kPa, Po₂ 49.4 kPa, bicarbonate 13.7 mmol/l, base excess (BE) −16.0 and lactate 16 mmol/L. Initial creatine kinase was >16000 u/l, urea 6.9 mmol/l, serum creatinine 248 μmol/l and serum potassium 6.7 mmol/l.

Haemofiltration was commenced on arrival to intensive care unit for renal failure secondary to rhabdomyolysis. Continuous veno-venous haemofiltration was used with filtration fraction of 25–30%, which was initially effective in reducing serum myoglobin.

Initially, it was thought that the left thigh swelling was secondary to misplacement of femoral line in left groin and the fluid that had been infused at this site. However, it quickly became apparent that there was also swelling of the right thigh and leg and a diagnosis of compartment syndrome was suspected. Doppler ultrasound was used to look for femoral arterial and/or venous clots but none were found. An orthopaedic consult was requested urgently.

Ten hours after admission to the unit, plasma creatine kinase (CK) increased abruptly to 187 384 U/l.

Orthopaedic review revealed a left calf compartment pressure of 66 mm Hg and left thigh compartment pressure of 67 mm Hg, right calf 69 mm Hg and right thigh 67 mm Hg. A diagnosis of acute compartment syndrome of both lower limbs was confirmed and bilateral emergency fasciotomies were performed in both thighs and calves. Despite fasciotomies, there remained no perfusion to both feet.

There was also continuing rhabdomyolysis despite being on haemofiltration and patient was on maximal inotropic support within hours of admission to the PICU. An echocardiogram 40 min after admission revealed an underfilled heart, despite three further fluid boluses on admission. A portable computed tomography (CT) scan of the patient’s head on day of admission revealed multiple low density areas in the cerebellar region and generalised cerebral oedema; overall the appearance was suggestive of multiple infarcts secondary to a meningoencephalitis.

Investigations

• Full blood count, film and clotting.

• Creatine kinase.

• Urea and electrolytes including phosphate, calcium, potassium, urate.

• Blood glucose.

• Blood, urine tracheal aspirates for microscopy and culture.

• Nasopharyngeal and throat swabs for immunofluorescence for viral pathogens.

• Urine dipstix for pH, ketones, glucose and blood. If dipstix positive for blood yet no red blood cells are seen on microscopy then myoglobin is present.

• Regular assessment distal pulses and perfusion.

• Measurement of compartment pressures where indicated.

• Metabolic tests as indicated—determination of acylcarnitines and carnitine values were performed in our patient, looking for medium chain Acyl-CoA dehydrogenase deficiency (MCAD) as he had had hypoglycaemia on presentation and no ketones in his urine.

Differential diagnosis

Causes of rhabdomyolysis in children under 9 years of age include trauma, infections, inherited metabolic conditions and inherited or acquired muscle diseases (for example, dermatomyositis).⁶ Influenza A and B are the most common causes of viral myositis in children but progression to rhabdomyoloysis, renal failure and compartment syndrome is rare. More commonly severe sepsis and septic shock can be associated with muscle ischaemia and subsequent rhabdomyolysis, compartment syndrome and renal failure.

Treatment

The damaged muscle cells sequestrate water from the plasma causing further swelling from massive fluid accumulation and risk of compartment syndrome, but this also depletes the intravascular volume. The primary determinant in the development of renal failure in these patients is a decrease in renal blood flow and hence the glomerular filtration rate (GFR). The patients most at risk of renal failure therefore are those who have concomitant vomiting and dehydration, as our patient did.

• Restore circulating volume with isotonic saline and then titrate fluid needs with urine output.

• Broad spectrum antibiotics to cover more common causes of sepsis in this age group.

• Give sodium bicarbonate cautiously to alkalinise the urine to help prevent precipitation of myoglobin in the tubules (aim urinary pH >6.5).

• Use loop diuretics and fluids to maintain a urine output of > 2–3 ml/kg/h.

• Measure compartment pressures and if >30 mm Hg consider fasciotomies early.

• Correct electrolytes disturbances (common) to prevent dysrhythmias and clotting abnormalities (disseminated intravascular coagulation occurs commonly once renal failure is established and its pathophysiology appears directly related to endothelial damage and dysfunction caused by the disseminated virus).⁵

• Once renal failure is established renal replacement therapy will be required.

• Supportive therapies for multiorgan failure as indicated.

• Treatment with neuraminidase inhibitors such as oseltamivir may limit disease severity^8,9 if given early in patients with known influenza A, H3N2; unfortunately this was not an option for our patient who died before the causative organism was isolated.

Outcome and follow-up

Despite inotropic, renal and fluid support the patient’s condition deteriorated and 40 h after admission he suffered a cardiorespiratory arrest. This lasted 4 min and required two doses of epinephrine and fluid filling.

At the time of arrest, the patient was receiving infusions of 1.6 μg/kg/min epinephrine and 1.2 μg/kg/min nor epinephrine.

There was ongoing bleeding from the fasciotomy wounds in both legs and continuing coagulopathy due to disseminated intravascular coagulation (DIC), which was difficult to correct. It was also noted at this time that compartment pressures in the upper limbs and buttocks were >40 mm Hg bilaterally, confirming development of further compartment syndromes in these muscle groups. The muscle in both legs and thighs was now necrotic on direct inspection and most likely causing persistent systemic inflammatory response syndrome, but our patient was not stable enough for surgery for debridement of the necrotic tissue.

In view of the patient’s ongoing deterioration despite maximal support and therapy, and after discussion with the parents, a decision was made to not escalate treatment further and not to resuscitate in the event of a further cardiorespiratory arrest. The patient died 4 h later from an asystolic cardiac arrest 48 h after admission to the PICU. Cause of death was multiorgan failure secondary to disseminated influenza A. Tracheal aspirates later isolated influenza A, H3N2.

Discussion

This case illustrates a rare but devastating complication of a common illness leading to death in a previously healthy child. In influenza, myositis is caused by direct viral infection of the muscle (and muscle specific toxin may be generated), the muscle cells swell following injury, and the compartment syndrome results from elevated pressure in a closed fascial space. After fasciotomies muscle swelling may continue, as there is primary muscle pathology. Extensive compartmental involvement can also be a feature of influenza associated myositis.^4,5 The classic symptoms of severe muscle pains, weakness and urinary discoloration are not always present in children and may be difficult to elicit—for example, our patient had a reduced level of consciousness. If the patient survives, the myositis usually improves within 6 weeks.

Compartment pressures in cases of viral induced myositis increase rapidly and need to be frequently assessed. Normal compartment pressures should be <8 mm Hg. Our case had initial pressures of >60 mm Hg in the lower limbs and this was within hours of admission to the PICU. In our patient, compartment syndrome developed extremely rapidly but it is possible that earlier fasciotomies may have been beneficial; however, the clinical setting was that of an extremely unstable patient with established multiorgan failure and DIC.

There are a few case reports of rhabdomyolysis, renal failure and compartment syndrome in adults, but numbers are small and not all cases were fatal.^1,2,5 Viral myositis is uncommon in adults.

The literature on the condition in children is similar with only a few case reports.^4,7 However, there are two studies, which offer more insight into the problem. Firstly, Mannix et al conducted a 10 year review of cases of rhabdomyolysis in children (191 cases were identified) and found that 39% of cases in children under 9 years of age were due to viral myositis; influenza A and B were the most common viral cause.⁶ Of the entire cohort only nine children with a CK above 1000 u/l developed renal failure and all recovered. There are no reports of rhabdomyolysis, renal failure and compartment syndrome associated with influenza infection in children vaccinated against influenza.

Bhat et al studied all deaths in children due to influenza in the USA between 2003 and 2004.¹⁰ One hundred and fifty-three children died in this 2 year period and 47% of the children had been previously fit and well, but only 5/153 patients had had myositis or rhabdomyolysis. During this season the predominant virus was influenza A (H3N2), which is associated with increased mortality and morbidity. In the USA, influenza associated deaths have been nationally reportable since October 2004 and influenza vaccination is now recommended for all children between 6 months and 18 years.¹¹

In the UK, present recommendations for vaccination against influenza are for children over 6 months old with chronic medical conditions.¹²

Learning points

• Recent data suggest that paediatric deaths due to influenza are more prevalent than thought in previously fit and well children.^9,13

• It is important to keep children with severe influenza well hydrated to ameliorate or prevent renal complications.

• If a child with influenza complains of severe muscular pain or leg pains severe enough to discourage walking:

• • ask the parents about urine colour

  • check distal pulses and perfusion to all limbs to exclude compartment syndrome

  • check plasma CK to look for rhabdomyolysis.

• If compartment syndrome is suspected or diagnosed early orthopaedic referral and intervention such as fasciotomies may prevent subsequent muscle necrosis.

• Rhabdomyolysis and compartment syndrome due to influenza A (H3N2) has not been reported in children vaccinated against influenza.