Neurogenic pulmonary oedema (NPO) is a life-threatening condition in which acute pulmonary oedema occurs as a result of significant injury to the central nervous system (CNS) (Davison et al, 2012). The connection between central nervous system dysfunction and cardiopulmonary complications can be traced back to Harvey Cushing in 1901, who identified specific nervous system responses to significant rises in intracranial pressure (ICP) (Cushing, 1901). Soon after this discovery emerged the first documentation of links between acute neurogenic pulmonary oedema and epilepsy (Shanahan, 1908), although NPO is now also associated with subarachnoid and subdural haemorrhage (Veeravagu et al, 2014; Yamagishi et al, 2014), traumatic brain injury (Bahloul et al, 2006), spinal cord injury (Leal Filho et al, 2005), bacterial meningitis (Soler et al, 1995; D'Souza and Kerr, 2001), and multiple sclerosis (Padley et al, 2012; Plummer and Campagnaro, 2013), among others. It is widely recognised that NPO is under-reported clinically, possibly due to under-recognition because of its lack of specific diagnostic characteristics (Davison et al, 2012), and possibly because much information on NPO is garnered from reports on individual cases or autopsies (Bahloul et al, 2006), and thus it is virtually impossible to establish the true incidence of the syndrome.
Aetiopathogenesis
Neurological conditions that cause an abrupt and rapid increase in ICP are closely correlated with, and therefore at greatest risk of, NPO (Davison et al, 2012). There are indications that the cervical spinal cord, brainstem, and hypothalamus are the centres for the triggering of NPO (Baumann et al, 2007), and it is believed that the neuronal insult stimulates a hyperactivation of the sympathetic nervous system through these centres, prompting the release of catecholamines such as epinephrine and dopamine (Sedý et al, 2008). This, combined with the autonomic response to increased ICP—such as the substantial, if transient, venous and arterial vasoconstriction (Baumann et al, 2007)—are pivotal in the development of NPO (Davison et al, 2012). Although the mechanistic process at the level of the pulmonary vascular endothelium remains elusive (Davison et al, 2012), five principle theories regarding the development of NPO have been proposed:
Neuro-cardiac NPO
Originally asserted by Connor (1969) and supported by multiple subsequent studies, it has been suggested that neurologic insult directly causes focal necrosis to the myocardium—damage to which is evident in the electrocardiograms (ECG) of a significant proportion of patients with traumatic head injury (Bahloul et al, 2006). Similar ECG abnormalities attributed to the impairment of left ventricular function were also discovered in patients with subarachnoid haemorrhage who otherwise had no pre-existing cardiac problems (Mayer et al, 1999), and are considered of sufficient significance as to provide prognostic indicators of patient mortality in those with this condition (Sugimoto et al, 2008). As noted previously, there is massive sympathetic system activation following the CNS injury, but it is the catecholamine surge that is thought to induce the direct injury to the myocardium, as cell death stems from a toxic overload of myocyte calcium caused by a high concentration of norepinephrine in the interstitial tissue (Zaroff et al, 2000). This then causes haemodynamic instability and the associated loading of fluid (Baumann et al, 2007).
Neuro-haemodynamic NPO
Unlike the above theory, the neuro-haemodynamic argument suggests instead that ventricular impairment is caused indirectly by the sudden rises in pulmonary and systemic pressures following the neurogenic insult (Davison et al, 2012). Studies on animals with a pharmacologically-induced sympathetic efflux have noted that the left ventricle becomes unable to attenuate the aortic and pulmonary pressures, thereby causing a failure in effective pumping (Sarnoff and Sarnoff, 1952). Hydrostatic pulmonary oedema is subsequently caused by the shift in blood from the high-resistance systemic circulatory system to the lower-resistance pulmonary circulatory system (Sarnoff and Sarnoff, 1952).
Blast theory
The above hydrostatic theory, however, is, solely, unable to explain the red blood cells and proteins routinely present in the pulmonary fluid of patients with NPO, which can only be accounted for by changes in vascular permeability (Davison et al, 2012). The ‘blast theory’, therefore, was proposed by Theodore and Robin (1976) to incorporate vascular leakage into hydrostatic theory (Davison et al, 2012). It suggests that the rise in intravascular pressure, predicated by the neural insult, may be sufficient to cause barotrauma, damaging the pulmonary endothelium and allowing protein-rich plasma and red blood cells into the alveoli and interstitial space (Baumann et al, 2007; Sedý et al, 2008). Animal studies support this theory (Maron, 1989; Maron et al, 2001), demonstrating additionally that the severity of the permeability correlates to the level of pressure (Maron et al, 2001), although the extent of pulmonary hypertension that is required for the development of NPO varies across different species (Maron, 1989).
Pulmonary venule adrenergic hypersensitivity
The fourth theory posits that, rather than NPO developing as the result of hypertension and reduced ventricular contractility, the sympathetic surge directly damages the pulmonary endothelium, causing NPO to occur irrespective of any other systemic variations (Davison et al, 2012). a- and b-adrenergic receptors are present in the pulmonary vascular bed, rendering plausible the hypothesis that the neural surge could undermine the structural integrity of the endothelium (Davison et al, 2012)—a theory supported by the canine studies of McClellan et al (1989). Similarly, neuropeptide Y and endothelin-1—both potent vasoconstrictors—have a strong association with endothelial permeability (Hamdy et al, 2000; Baumann et al, 2007), with one study finding vascular permeability of the lungs increasing 22-fold in rat models after the introduction of endothelin-1, resulting in pulmonary oedema (Poulat and Couture, 1998).
| Presenting complaint | 8-year-old female: reported fitting at school (lasting approximately 8 minutes)—second fit that day (the first lasted approximately 2 minutes). |
| History of presenting complaint | Staff administered paraldehyde (patient's own medication) prior to arrival; patient's care plan stated that patient must attend hospital after administration of paraldehyde. |
| Medical history | Dravet syndrome; syndrome-related symptoms including epilepsy, physical developmental delays, behavioural difficulties (such as hyperactivity), developmental delays in communication skills and acquisition of language, and ataxia; ketogenic diet. |
| Allergies | None. |
| Medication history | Sodium valproate (Epilim); levetiracetam (Keppra); paraldehyde. |
| Observations | Glasgow Coma Scale: 8 (eyes 2, motor 4, verbal 2), improving to 15 prior to hospital arrival. |
| On examination | Upon recovery to GCS 15, patient was noticed to have a chesty-sounding cough which resolved completely within 15 minutes of onset. On further enquiry, patient's father stated that this was a regular postictal occurrence. Patient had no chest infection or evidence of a cold. |
Negative pressure postictal pulmonary oedema
Unlike the preceding theories, as the title suggests, this condition is specific to those suffering with epilepsy. Cases have been reported of postictal laryngospasm (Tavee and Morris, 2008), and it has been surmised that substantial inspiratory effort against a closed glottis may cause massive negative intrathoracic pressure that translocates fluid from the capillaries into the alveolar spaces, damaging the capillaries in the process (Lorch and Sahn, 1986; Kennedy et al, 2015).
CNS disorders associated with NPO
As noted above, NPO can stem from any CNS injury, but there are some disorders in which it is more predominantly observed, and so it is appropriate to focus on those:
Status epilepticus
It has been reported that approximately a third of patients with status epilepticus are also diagnosed with NPO, and the condition is strongly associated with sudden unexpected death in epilepsy (SUDEP): mild or extensive pulmonary oedema is invariably found in SUDEP post-mortems (Zhuo et al, 2012; Zhao et al, 2014) and it has been hypothesised that NPO may be a significant contributing factor to the cause of death (Kennedy et al, 2015). Furthermore, Kennedy et al (2015) suggest there is a correlation between the duration of the seizure and the presence of pulmonary oedema in tonic-clonic fits. Two aspects are particularly interesting in relation to the case study outlined above: firstly, that in non-SUDEP patients NPO predominantly develops in the postictal stage (Baumann et al, 2007), and secondly, the assertion that paediatric NPO is primarily attributed to status epilepticus (Mulroy et al, 1985). Although it was not possible to formally confirm a diagnosis of NPO, anecdotally the aetiology and symptoms correspond closely with the postictal symptoms exhibited by the patient.
Acute subarachnoid haemorrhage
There is great variation in the documentation of pulmonary oedema in patients with acute subarachnoid haemorrhage (SAH), ranging from 8%–23% (Solenski et al, 1995; Muroi et al, 2008), but while it is associated with increased mortality (Bruder and Rabinstein, 2011), it is acknowledged that it cannot be independently considered a predictor of clinical outcome (Friedman et al, 2003; Bruder and Rabinstein, 2011).
Traumatic brain injury
Moutier (1918) was the first to associate NPO with head injury after observing a rapid onset of pulmonary oedema in soldiers with cranial bullet wounds during World War I, and similar occurrences were reported in Vietnam War soldiers with isolated gunshot injuries to the head (Simmons et al, 1969). A more recent report found an incidence of NPO in 32% of patients with isolated head injuries who died on scene, rising to 50% in patients who died within 96 hours (Rogers et al, 1995), and others have claimed a general incidence of NPO of 20% in traumatic brain injuries (Mascia, 2009). In brain death patients, the lungs are particularly susceptible to numerous insults (Kotloff and Thabut, 2011), and NPO and infection constitute the two principle contraindications to lung harvesting in this group of patients (Baumann et al, 2007).
Clinical presentation
Problematically, the symptoms of NPO are non-specific, and the patient may present with an abrupt onset of dyspnoea, chest pain, nausea and/or vomiting, and a fear for their life (Sedý et al, 2008). Initially on examination, tachypnoea, basal pulmonary crackles, hypoxaemia, hypercapnia, raised systolic blood pressure with normal jugular venous pressure, decreased level of consciousness, pink frothy sputum and/or haemoptysis may all be observed (Baumann et al, 2007; Sedý et al, 2008; Seyal et al, 2010; Davison et al, 2012), and additionally there is evidence for the possibility of unilateral NPO (Perrin et al, 2004). Importantly, there will be an absence of any signs of inflammation (Sedý et al, 2008). Tachycardia has been reported in patients presenting with NPO (Baumann et al, 2007), but, conversely, as the result of increased ICP, so has pronounced baroreflex bradycardia which has been observed prior to, as well as during, the onset of NPO (Sedý et al, 2009). As mentioned above, studies have demonstrated an association between neurological insult and ECG changes. However, because the ECG changes reported manifest variably, with descriptions of ST-segment deviation, inverted T-waves, prolonged QT, and pathological Q-waves, in addition to the tachy-and bradycardias (Mayer et al, 1999; Sugimoto et al, 2008), there is insufficient consistency to consider ECGs as a diagnostic component of NPO (Baumann et al, 2007).
Evidence suggests that NPO can either occur early, with symptoms developing within minutes of the neurological injury, or, less commonly, be delayed, with symptom onset occurring up to 24 hours post-injury (Davison et al, 2012). Symptoms frequently resolve spontaneously within approximately 24–72 hours depending on how severe the CNS injury is (Baumann et al, 2007; Davison et al, 2012), although, if the ICP remains unrelieved, the NPO will continue (Davison et al, 2012). In postictal cases, both onset and resolution of NPO may occur quickly (Seyal et al, 2010), although there have been reports of recurrent seizure-related NPO (Darnell and Jay, 1982).
Fundamentally, ‘pure’ NPO itself is an exclusionary diagnosis (Davison et al, 2012), and therefore can only be definitively established if non-cardiogenic pulmonary oedema is confirmed within the context of CNS insult (Antoncic et al, 2015), although clinicians should also be aware of differential diagnoses including aspiration pneumonia, and lung injury caused by ventilation/ventilators (Baumann et al, 2007).
Airway management
Treatment available to ambulance clinicians in the presence of NPO is limited, particularly in relation to pharmacological interventions and the restrictions involved in CNS management. However, after making the usual assessments of airway, breathing and circulation (Association of Ambulance Chief Executives, 2013), it is vital to treat the underlying neurological trigger (such as convulsions), if possible, as a priority (Baumann et al, 2007). If NPO is discovered, the patient should be oxygenated appropriately, and the method of ventilation should be determined by the severity of the condition and the patient's Glasgow Coma Scale, with a low threshold for intubation in cases of severe NPO (Baumann et al, 2007). In this circumstance, the judicious use of positive end-expiratory pressure (PEEP) is recommended (Baumann et al, 2007): lower levels of PEEP have not been found to be detrimental to cerebral perfusion pressure (Huynh et al, 2002), although care should be taken not to cause alveolar hyperinflation as this can increase ICP significantly due to the subsequent rise in PaC02 (Mascia et al, 2005).
Pharmacological treatment
In-hospital drugs for the treatment of NPO predominantly include osmotic diuretics, steroids, and anti-a-adrenergic agents, all of which have been found to aid oxygenation (Davison et al, 2012), in addition to those used to treat the underlying neurological injury. However, some of the drugs discussed in studies on NPO are those already included within the current ambulance clinical repertoire, and thus a brief summary of the use of those drugs within that clinical context is given as follows:
Sodium chloride 0.9%
Particularly in cases with a traumatic aetiology where hypovolaemia may also need to be managed, the use of sodium chloride should be cautious, as overloading the circulating volume may exacerbate or cause pulmonary oedema (Davison et al, 2012). It is highly recommended, therefore, that sodium chloride should administered as per the ambulance clinical guidelines (Association of Ambulance Chief Executives, 2013).
Glyceryl trinitrate
Although large doses of nitrates have been found to be effective in reducing NPO as a result of vasodilation (Chen et al, 1992), glyceryl trinitrate (GTN) is indicated solely for the cardiogenic form of pulmonary oedema (Association of Ambulance Chief Executives, 2013), and there is no mention of its specific use in any literature found on NPO.
Furosemide
Despite reports of its use in hospital as a continuous infusion to treat patients with NPO (Schwartz et al, 1999; Nguyen et al, 2012), ambulance guidelines state specifically that furosemide is also only indicated in ‘Pulmonary oedema secondary to left ventricular failure’ (Association of Ambulance Chief Executives, 2013: 303), and thus is not available to ambulance clinicians in the context of NPO. However, generally, within hospital, osmotic diuretics such as mannitol appear to be used in preference to loop diuretics such as furosemide (Pyeron, 2001).
Atropine
Interestingly, it has been hypothesised that it may be beneficial to administer a high dose of atropine soon after the onset of NPO in an attempt to rectify baroreflex bradycardia, thus reducing the pulmonary hydrostatic pressure by improving cardiac pumping function and subsequently relieving the NPO (Sedý et al, 2009). Sedý et al (2009) state additionally that if the use of atropine was to be implemented, it would have to be administered while the patient was intubated in order to prevent the glottis narrowing, causing increased respiratory resistance and a corresponding increase in pulmonary venous pressure. Initial experiments on rats with spinal cord compression have found that atropine attenuates the characteristic associated bradycardia and thereby prevents the development of NPO, leading to the hypothesis that a similar result may occur on humans if atropine is administered soon after the CNS insult (Sedý et al, 2015).
Naloxone
Endogenous opioids such as endorphins have been demonstrated to exacerbate pulmonary vascular permeability, thereby increasing the quantity of pulmonary fluid in experiments on animals with raised ICP (Sedý et al, 2015). Naloxone, as an opioid antagonist, has been noted to provide a protective role in the development of NPO (Sedý et al, 2015).
Conclusions
It is evident that NPO can have significantly detrimental implications for the clinical status of the CNS-compromised patient and should be considered and incorporated as a standard component of the paramedic's neurological assessment. However, care should be taken to distinguish NPO from cardiogenic pulmonary oedema and other differential diagnoses prior to committing to a specific plan of action. Treatment itself is inhibited not solely by under-recognition, but also by a lack of understanding of the aetiology which is a prerequisite for successful pharmacological intervention, and this inevitably undermines ambulance service provision within this context. Furthermore, treatment of the underlying neurological injury remains the clinical priority for the resolution of NPO, and thus direct treatment of NPO remains secondary provided it does not significantly compromise airway, breathing, or circulation. However, if the patient in the case study was exhibiting NPO, this brings into perspective the possible prevalence of the disorder, even in relation to ostensibly simple neurological conditions, therefore justifying the highlighting of this condition.