The role of inhaled nitric oxide beyond ARDS.

Patients with traumatic brain injury complicated by acute respiratory distress syndrome (ARDS) are not uncommon in intensive care unit (ICU). The ventilatory management of patients combined with both of these catastrophic conditions is not straightforward. Evidence-based permissive hypercapnia strategy for ARDS could be fatal in patients with intracranial hypertension. Adjunctive use of inhaled nitric oxide (INO) is well-defined as a rescue therapy in severe ARDS, but its specific role in intracranial hypertension is somewhat uncertain. We report a case, which following traumatic brain injury developed both intracranial hypertension and ARDS. INO was given for ARDS, but coincidentally it also improved the raised intracranial pressure (ICP) and patient's neurological outcome. The case report will be followed by literature review on the role of INO in raised ICP.

Introduction

Acute respiratory distress syndrome (ARDS) is not an uncommon feature in patients with traumatic brain injury. The management plan for ARDS requires permissive hypercapnia, whereas, raised intracranial pressure (ICP) is managed by normocapnia or hypocapnia, which in a way are contradictory to each other.[1]

The role of inhaled nitric oxide (INO) in ARDS is well-described, while in raised ICP is not yet established. We report a case which showed improvement of raised ICP and ARDS following traumatic brain injury (TBI) with INO.

Case Report

A 13-year-old boy was brought to the emergency room with multiple injuries following a motor vehicle accident. He was intubated because of low Glasgow Coma Scale (GCS; 5/15). Pupils were equal and reactive, blood pressure 100/55 mmHg, pulse 110 per min, oxygen saturation 94% on 0.6 FiO2, and respiratory rate 16 per min. Trauma X-ray series showed fractures of the left femur and pelvis (stable fracture). Computed tomography (CT) brain showed mild cerebral edema with no midline shift. Patient was transferred to the intensive care unit (ICU) for further management.

Patient was sedated with midazolam 4-6 mg/h and fentanyl 100-150 μ/h. The ventilator (Dräger, Infinity C500, Germany) settings in the ICU were as follows; assist control mode, respiratory rate 14 per min, tidal volume 7 ml/kg (according to ideal body weight), inspiratory flow rate 45 l/min, positive end-expiratory pressure (PEEP) 5 cmH2O, and FiO2 0.5. Patient's weight and height were 60 kg and 160 cm, respectively (ideal body weight (IBW) 57 kg). Lung mechanics revealed high peak and plateau pressure (35 and 30 cmH2O, respectively).

After 24 h, patient's pupil became unequal and CT brain showed right temporoparietal epidural hematoma. Evacuation of hematoma was done, and patient was transferred back to ICU with ICP monitoring device. Initial ICP and cerebral perfusion pressure (CPP) were 17 and 60 mmHg, respectively [Figure 1]. Post-surgery ventilator settings were assist control mode, rate 28, tidal volume 6 ml/kg, FiO2 1.0, and PEEP 8 cmH2O. Arterial blood gas showed pH 7.32, PaCO2 46, PaO2 65, HCO3 19 meq/L, and SpO2 was 93%.

Figure 1

Right temporoparietal acute epidural hematoma noted with maximum depth of 2.2 cm and causing mass effect

After 48 h, patient developed features of severe ARDS[2] [Figure 2]. Tracheal aspirate was negative for any organism. Lung protective ventilation strategy was started as follows; ventilatory rate 32 per min, tidal volume 5-6 ml/kg (300-350 ml), FiO2 1.0, and PEEP 16. This ventilatory setting led to increase in ICP from 17 to 28 and reduction of CPP from 60 to 45. Arterial blood gas showed pH 7.24, PaCO2 53, and PaO2 58. Cisatracurium was used at this stage to paralyze the patient with 0.3 mg/kg/h as maintenance dose after bolus of 0.2 mg/kg. Train of four was also monitored. 20% mannitol (1 g/kg) was used 8-hourly for 24 h with monitoring of serum sodium (target serum sodium: 150-155 mEq/L) and serum osmolality (target osmolality up to 320 mOsm). Norepinephrine was used for 24 h for keeping mean arterial pressure (MAP) above 90 mmHg.

Figure 2

Bilateral lung infiltrate

Patient was started on INO to improve pulmonary mismatching. INO was started after discussion with family members. It was started with 10 ppm, then gradually built up to 35 ppm. Next 12-24 h, PaO2 and PaCO2 improved. ICP also showed gradual improvement from 18 to 5. Blood gases were as follows: pH 7.37, PaCO2 40, and PaO2 128. PEEP reduced from 16 to 10 and FiO2 from 1.0 to 0.6 [Table 1 and Figure 3].

Table 1

Change in ABGs, ICP, CPP, FiO2, and PEEP before and after INO

Figure 3

Change in ABGs, ICP, CPP, FiO2, and PEEP before and after the use of INO. ABG = Arterial blood gas, ICP = intracranial pressure, CPP = cerebral perfusion pressure, PEEP = positive end-expiratory pressure, INO = inhaled nitric oxide

INO was discontinued after 1 week, and patient was weaned off from the ventilator. Post-extubation patient remained conscious with no neurological deficit. Repeat CT head was normal. Further stay in ICU remained uneventful, and then patient was transferred to the ward. Patient remained in hospital for 2 months as he developed an hospital-acquired infection and then shifted home.

Discussion

ARDS following TBI is not an uncommon complication. It can lead to hypoxemia and decreased oxygen supply to the brain that can further worsen brain injury.

The management for raised ICP requires PaO2 around 100, PaCO2 between 30 and 35, and CPP 50-70 mmHg.[3] On contrary, “permissive hypercapnia” may be required for patients with severe ARDS.[4]

INO is increasingly used in ICUs for patient with ARDS, but its use in traumatic brain injury patients is not yet clear. There are two case reports (one in adult and other in a child);[56] so far, highlighting the successful use of INO in patient with severe traumatic brain injury complicated with ARDS.

The role of INO is still experimental in traumatic brain injury. It is a known fact that ischemia is one of the leading causes of secondary brain damage, and worsening of cerebral blood flow (CBF) is a dominating feature in the progression of pericontusional ischemic changes.[7] The role of a selective vasodilator with action on hypoxic/ischemic tissue would certainly be a viable strategy for the treatment of pericontusional ischemia; however, such a therapeutic option is not yet available. Terpolilli et al.,[89] observed the protective effect of INO as it selectively dilates cerebral resistant vessels in hypoperfused areas, and thus, improved collateral blood circulation in the brain. It was hypothesized by Papadimos[10] that INO could improve metabolic function and prevent death of the ischemic penumbra under conditions of transient reduction of CBF. Furthermore, regional vascular protective effects were nicely described by Cannon et al.[11] As a selective cerebral vasodilator, it may cause inverse steal or Robin Hood effect[12] in brain injured tissue that can play as a neuroprotective role.

Vavilala et al.,[6] first, described the safe use of INO in TBI. Papadimos et al.,[5] successfully used INO to decrease ICP in a patient with severe TBI complicated by ARDS. This study further elucidated the anti-inflammatory and neuroprotective effect of INO in traumatic brain injury.

In our case report, the clinical scenario for using INO was not very much different from the case presented by Papadimos et al.,[5] but interestingly in our case the timing of initiation of INO was early with encouraging cerebral outcome. The use of INO showed concomitant reduction of arterial PaCO2 and ICP, which lead to improvement in CPP. This improvement in ICP and CPP can be hypothetically correlated to improvement in PaCO2 and PaO2, but the cerebral protective effect of INO is not new in the literature, though it is still limited to animal studies and case reports. This case report not only emphasized the early use of INO in TBI complicated with severe ARDS and raised ICP, but it also opens the discussion to use INO as one of the cerebral protective measures in future.

In conclusion, INO in principle can be considered for improvement of cerebral perfusion in patient with raised ICP particularly following TBI. More clinical studies, particularly randomized clinical trials (RCTs) are needed to validate it further.