High Frequency Oscillation – Shaken by Bad News!

oscillatorSummary: Two Papers Published Online in the NEJM, OSCILLATE and OSCAR, have failed to demonstrate that HFOV benefits patients with ARDS. In the OSCILLATE study there was an 11% increase in 28 day mortality (NNH 9). HFOV should not be used in routine management of patients with ARDS.

For the past two decades many intensivists have used an “open lung” approach to managing hypoxaemia in ARDS. This approach involves using high levels of PEEP, inverse ratio ventilation (IRV), airway pressure release ventilation (APRV) or high frequency oscillation ventilation (HFOV) – to keep severely injured lungs in a state of inflation during most of the respiratory cycle. “Open Lung” can be achieved by using high PEEP and small tidal volumes, or moderate levels of PEEP and long inspiratory times. In either case mean airway pressure increases. The most sophisticated method of using PEEP involves the construction of pressure volume curves and setting the PEEP above the lower inflection point. To date, the high PEEP approach has neither been proven to be better or worse than the incremental PEEP approach based on fiO2. However a 2010 meta-analysis has suggested that high PEEP may be beneficial in ARDS. With long inspiratory times oxygenation occurs principally during inspiration rather than expiration; functionally ventilation occurs on the expiratory limb of the volume-pressure curve.
There is good physiologic reasoning behind the open lung approach. Severe ARDs is characterized by massive atelectasis, increased lung water and pleural effusions; functional residual capacity is obliterated. As most gas exchange occurs in expiration, and end expiratory lung volumes are lost, open lung approaches use the inspiratory reserve volume. Further, it is widely believed that phasic opening and closing of injured lung units and uninjured adjacent units results in ventilator induced lung injury (atelectrauma). Open lung approaches prevent atelectrauma. The majority of ICUs utilize conventional ventilator strategies such as pressure support, pressure control (or bilevel) or volume assist-control in early ARDs. However, in patients with severe and refractory hypoxic respiratory failure, units differ between using high PEEP and so called “advanced” modes to maintain oxygenation. Despite the conceptual attractiveness of IRV, APRV and HFOV there has always been an evidence gap in support of these modes: nobody knows how much the lung stretches. There is no easy way to measure end inspiratory lung volumes and hence to evaluate the risk of volutrauma. Proponents of “advanced” modes will argue that absence of evidence does not mean absence of efficacy: clearly open lung modes of ventilation improve oxygenation – so this must be good. However, we have decades of data suggesting that prone positioning improves oxygenation, but not outcomes.

After a long wait, we have now seen the publication of two studies on HFOV – the multi-national OSCILLATE study, and UK based OSCAR trial. The results are not good.


Background and Methods: This was a multi center trial of 38 hospitals in Canada, the United States, Saudi Arabia, Chile, and India from July 2009 thru August 2012. Patients were eligible for inclusion if they had had an onset of pulmonary symptoms within the previous 2 weeks (i.e. this was an acute illness), had been intubated, had hypoxemia defined as a PaO2/FiO2 (PF) ratio of ≤200, with an FiO2 of ≥0.5), and had bilateral infiltrates on CXR. These criteria must have been met within the previous 72 hours. The authors were careful – patients who met criteria were put on pressure control ventilation, TV 600ml, FiO2 0.6 and PEEP 10cmH2O. If, after 30 minutes, the PF ratio was still below 200, the patients were enrolled in the trial. Patients were randomized to HFOV or conventional ventilation (CV). The patients were remarkably well balanced at baseline – and very sick – with mean Apache II scores in both groups of 29.

Technique: a recruitment maneuver was performed initially (40cmH2O for 40 seconds) then HFOV was commenced at a mean airway pressure of 30 cmH2O, adjusted to keep the PaO2 between 55 to 80 mm Hg (7.3 to 10.5 kPa). The frequency was adjusted to keep the pH above 7.2. Once mean airway pressure (mPaw) dipped below 24 cmH2O conversion to CV was considered; if mPaw went below 20cmH2O – conversion was mandatory. The CV group received a recruitment maneuver, then pressure controlled ventilation with TV 6ml/Kg and PEEP adjusted according to protocol. Initial PEEP was 20cmH2O. Patients could also receive volume assist control or pressure support ventilation. For patients with good compliance and gas exchange (presumably during the weaning phase), the investigators did not set limits for tidal volumes. A weaning protocol governed both limbs.

Results: the primary outcome was in-hospital mortality. The study was stopped early because of increased risk in the study group. At the time of termination, 571 patients had been enrolled, of whom 548 had undergone randomization: 275 to the HFOV group and 273 to the control-ventilation group. A total of 129 patients (47%) in the HFOV group, as compared with 96 patients (35%) in the control group, died in the hospital (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005) – an absolute risk INCREASE of 12%! This was independent of any other risk factor other than HFOV and was consistent at 28 days. Indeed 28 day mortality was 40% in HFOV group (which is not particularly bad) versus 29% (which is really excellent) in the conventional ventilation group – absolute risk increase 11% – number needed to injure 9. The duration of hospital stay for survivors was, on average, 5 days fewer in the CV group (although statistical significance is not reported) 25 versus 30 days.

Did HFOV have a physiological effect? Yes – patients almost immediately needed more vasopressors, more sedation and more neuromuscular blockade. There were fewer cases of refractory hypoxaemia but this had no statistically significant impact on outcomes.

My Impression

So, what to make of this study? Firstly, let us be clear – this was an excellent study (that we were all awareards of) performed by experts in the field of mechanical ventilation, who have a long track record of publication and interest in HFOV. They were not expecting the published results. This is a significant setback to our understanding of ARDS and interventions to rescue patients from severe hypoxaemia. Among my critical care colleagues, there are those of us who are proponents of ARPV and those of us who use HFOV. The published results ask as many questions about APRV as they do about oscillation. Can the worse outcomes be explained by increased doses of vasopressors and more sedation? No, I don’t believe it to be so: it is inconceivable that increased drug utilization could explain an 11% risk increase at 28 days. It is more likely that HFOV exacerbates ventilator induced lung injury (VILI).


The OSCAR study took place in the UK and included nearly 800 patients that had PF ratio <200 and wereOscar randomized to HFOV or CV. There was no significant between-group difference in the primary outcome, death at 28 days, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional-ventilation group (P=0.85). In other words – HFOV did not benefit these patients. Patients enrolled in this study had an average Apache II of 21 – lower than Oscillate – but had equally bad gas exchange when recruited. Although there was an increase in the use of muscle relaxants, there was no evidence of increased vasopressor requirements.

Of interest, patients in OSCAR had similar (although worse) 28 day mortality rates to those in the HFOV arm of the OSCILLATE study. It is worth looking at the LOV and EXPRESS trials for comparison. The EXPRESS trial had slightly older patients (60y both groups) with better gas exchange – PF ratio 143 and 144. Twenty eight day mortality was 31.2% and 27.8% (lower in high PEEP approach but not significant). The LOV study had patients in the same age range as both of these studies, but the PF ratios were significantly higher (144 in both groups); Apache II scores were 24 and 25 (patients were sicker than OSCAR). Mortality rates for all cause in hospital were 36.4% and 40.4% (again not significant). The lower end outcome is similar to the conventional group (and indeed had similar vent strategy to that group) in OSCILLATE. This suggests that the better outcomes in the conventional group in OSCILLATE accurately reflect true outcomes, and that the 28 day mortality in the LOV trial over-estimates outcomes at hospital discharge. But, can the difference in gas exchange really explain why the outcomes in OSCAR, in the conventional group at least, were 10% worse than EXPRESS? I don’t know – but comparing OSCILLATE to OSCAR – a 29% 28 day mortality (similar to LOV) is substantially lower than the 41% in the UK trial. These data suggest that the conventional group in that study did worse than expected. And, if this were the case, then HFOV was harmful in the OSCAR study too: the mortality rate for HFOV was essentially the same in both studies. Ok that might be conjecture – but take my point: a 41% mortality rate for ARDS is very high in the setting of a randomized controlled trial. For example, in the original ARMA trial the mortality rate in the control group (high TV) was 39.8% versus 31%; PF ratios 138 and 134. In the ALVEOLI trial the mortality rates were 24.9% (high PEEP) and 27.5%; PF ratios were 165 and 154. I have long argued that many of the patients in the NIH studies probably didn’t have ARDS – but the outcomes in OSCAR are the worst published in a multi center trial since the control group in Aries. Whatever way you look at it – this is all BAD NEWS for HFOV.

HFOV – is it safe?

One striking thing about these studies is how much the conflict with a previous meta-analysis of previously published papers. In that paper eight randomized controlled trials (n=419 patients) were included; the majority of patients had ARDS. Patients on HFOV had better oxygenation and reduced mortality (risk ratio 0.77, 95% confidence interval 0.61 to 0.98, P=0.03; six trials, 365 patients, 160 deaths). These results conflict directly with the outcomes of OSCILLATE and OSCAR: it is scary how meta-analysis of small studies (publication bias) can be misleading.

So, is it time to wrap up your oscillator and consign it to the ventilator graveyard? For ARDS – for routine practice – I think so.

1-forward-2-backFor rescue therapy or as a bridge to ECMO – HFOV may still have a role. Oscillation remains a useful therapy for broncho-pleural fistula and perhaps for severe lung contusion. But in other settings – I believe – use with extreme care. Is it time for a complete re-evaluation of open lung approaches in ARDS? Perhaps so – certainly before we put patients on extreme IRV modes (such as APRV) or HFO we should ask – “have I maxed out my options with conventional ventilation?”
One Step Forward – Two Steps Back.

Acute Respiratory Distress in the Recovery Room (tutorial)

Clinical Scenario: A 57 year old male undergoes upper abdominal surgery. He refused an epidural. The intraoperative course was uneventful. He was given 2mg hydromorphone in the OR. He was extubated, breathing 360 ml tidal volumes; arousable. Shortly after arrival to the recovery room, the patient develops acute respiratory distress. His respiratory rate increases to 33 breaths per minute, SpO2 is 92%, heart rate increases to 110 beat/min, blood pressure 98/50 mmHg. On examination, his pupils are pinpoint but reacting, he is moving air into both of his lungs but there is little air entry into his lung bases.

A non-rebreather facemask is placed: his SpO2 remains 92%.

1. Identify the problem

What is the principle diagnosis?

The patient is clearly in acute respiratory distress; however the cause and reversibility of the problem are unclear. It is imperative that the bedside clinician have a systematic approach to diagnosis and management. The cause of the problem may lie at any stage in the process of initiating a breath to exchanging gas. This tutorial focuses on the diagnosis.

Patients in recovery room with acute respiratory distress have one or more of the following three problems: failure to ventilate, as characterized by a high PaCO2, failure to oxygenate, as characterized by low PaO2, or failure to maintain their airway (figure 1). All three may co-exist: for example, a patient that receives excess opioids my hypoventilate, obstruct their airway due to opioids and carbon dioxide narcosis, and become hypoxic due to absorption atelectasis, failure to replenish alveolar oxygen and alveolar CO2 buildup. Nevertheless, the primary problem is failure to ventilate, due to central loss of respiratory drive. Hence, to make a diagnosis, one needs to identify the primary problem.

 Figure 1: Mechanisms of Acute Respiratory Distress in recovery room

There are three major components to the respiratory apparatus:

  1. Central chemoreceptors: in the brainstem that detect carbon dioxide and initiate the respiratory pump. This requires an intact brainstem and cervical nerve roots.
  2. The respiratory pump: the phrenic nerves (and on occasion the intercostals nerves) initiate diaphragmatic contraction. This requires and intact neuromuscular junction and sufficient diaphragmatic muscular tissue to increase the volume of the thoracic cavity. This leads to increased negative pressure within the pleura, stretching the alveoli. Flow of gas into the alveoli is known as ventilation.
  3. Alveolar-capillary interface: gas must flow across the alveolar capillary interface to enter and leave the blood. This is known as ventilation perfusion matching and is reliant on alveolar gas volume (particularly in end expiration – the functional residual capacity) and pulmonary blood flow.

The problem is either central – a problem of respiratory drive, peripheral – a problem of the respiratory pump, large airway – a problem of gas transfer, or alveolar – a problem of gas exchange (figure 2).

  1. Central Ventilation: the neurologic system is not activating respiration in response to an increase in arterial CO2 tension
  2. Peripheral Ventilation: the thoracic pump (chest and diaphragm) is not effective in guaranteeing adequate minute ventilation.
  3. Gas Transfer: air does not pass effectively from the upper to the lower airway due for example to increased airway resistance.
  4. Gas Exchange:
    1. Gas does not to pass effectively from alveoli to capillaries due to a pathologic process in the interstitial space (diffusion defect).
    2. Ventilation is being wasted – alveoli are being ventilated but not perfused: dead space ventilation or more air than the blood can utilize (high ventilation/perfusion (V/Q) ratio the extreme version being dead space ventilation).
    3. Blood flow is inadequately utilized and blood is passing through the lungs without coming into contact with aerated alveoli: perfused but not ventilated – shunt or ventilation falls behind blood flow (low V/Q ratio the extreme version being right to left shunt).

2. Understand the problem

What is the mechanism of injury?

Ventilation Failure

Failure to ventilate is the most common cause of acute respiratory distress in the recovery room. It is characterized by reduced alveolar ventilation which manifests as an increase in the PaCO2 > 50 mmHg (6.5kPa). The best method of classifying this is to follow the respiratory  pathways from the brainstem to the alveoli, and then ask whether a pathology exists at each particular site. Often patients have multiple problems: e.g. narcosis, pulmonary edema, pleural effusion, obesity


Central: loss of ventilatory drive due to general anesthetic agents (propofol principally), benzodiazepines, narcosis, stroke or brain injury

Spinal: spinal or epidural anesthesia; spinal cord injury, cervical – loss of diaphragmatic function, thoracic – loss of intercostals.

Peripheral: phrenic nerve injury in neck or thoracic surgery


Persistent neuromuscular blockade; diaphragmatic trauma; myopathic disorders – myasthenia gravis (patient post op thymectomy).

Anatomical Problems

Chest Wall – flail chest; intra-abdominal hypertension (abdominal packs placed).

Pleura – pleural effusions, pneumothorax (patient post op thoracic or retroperitoneal surgery: nephrectomy, abdominal aortic aneurysm, esophagectomy).

Airways – airway obstruction: laryngeal edema, inhalation of a foreign object (tooth or throat pack), bronchospasm.

Oxygenation Failure

Oxygenation failure occurs at a microscopic level at pulmonary capillary-alveolar interface. Two different injuries can occur at this level, either individually or in combination:

Diffusion abnormality – thickening of the alveoli (pulmonary fibrosis). There is an obstruction to effective gas exchange due to material in the interstitial space. The patient will have an antecedent history of hypoxemia.

Ventilation/Perfusion Mismatch: Dead Space Ventilation (or high V/Q): alveoli are ventilated but not perfused. This is unusual in the extubated patient, an usually results from significant hypovolemia


Figure 2 Causes of Respiratory Failure

Ventilation Perfusion Mismatch (figure 3): this occurs when lung units well perfused but poorly ventilated. The extreme version is right (as in right side of the heart) to left shunt (blood flows through the lungs without coming into contact with aerated lung tissue. This lung injury is resistant to oxygen therapy. This frequently occurs in patients that have upper abdominal or chest surgery secondary to segmental lung collapse – atelectasis. Atelectasis may actually be worsened by oxygen therapy, due to rapid reabsorption.

Less severe, and usually oxygen sensitive, ventilation-perfusion mismatch is the inevitable consequence of major surgery. The time constants in many lung units are altered due to edema in the lung tissue and secretions in the major and minor airways. This results in an alteration of the dynamics of gas transport: alveolar oxygen tension is slower to be replenished, carbon dioxide is more slowly removed.

Figure 3: Ventilation-Perfusion Mismatch. Alveolar unit A has normal ventilation and perfusion, hence the pulmonary capillary (arterial side) oxygen tension (PcO2) is 100mmHg (13kPa). Unit C is ventilated but not perfused. It does not contribute to gas exchange. Unit B is partially ventilated, but due to it’s long time constant (due to secretions), the alveolar oxygen tension is below normal, and the PcO2 is reduced to 70mmHg (9kPa). When all lung units are accounted for, the result is hypoxemia (PaO2 70mmHg/9kPa)

Figure 4: Oxygen therapy effectively treats ventilation perfusion mismatch by increasing the fraction of gas in the alveolus that is oxygen, thus increasing the PAO2 (alveolar O2). It also reverses pulmonary vasoconstriction and reduces dead space.

Figure 5: Right to left intrapulmonary shunt: in this example, 50% of the pulmonary circulation is flowing thru collapsed lung tissue. Because hemoglobin can only be saturated to 100%, regardless of the quantity of oxygen that is delivered to normal lung tissue, it is not possible to compensate for the intra-pulmonary shunt.

3. Differential diagnosis / Work the problem

How do you make the diagnosis?

Acute respiratory failure is usually a problem of either failure to oxygenate, as characterized by a low PaO2, or failure to ventilate, as characterized by a high PaCO2. Where hypoxemia and hypercarbia co-exist, oxygenation should be considered the primary problem.


Figure 6: Assessing the Patient with Acute Respiratory Failure

The key to making the diagnosis is to look at the patient’s breathing pattern. If the patient is taking slow shallow breaths, with normal synchrony between opening of the mouth to inhale and movement of the chest outwards and downwards, then the problem is most likely ventilatory failure secondary to central respiratory depression. This most commonly results from opioid administration, but may also follow the administration of midazolam/lorazepam or discontinuation of a propofol infusion.

If the patient is taking rapid shallow breaths, the problem is either ventilatory failure secondary to a peripheral problem or oxygenation failure secondary to ventilation-perfusion mismatch. The key to separating the two is the clinical circumstance and the presence or absence of hypoxemia (low SpO2 or requirement for high FiO2). In the absence of hypoxemia, a neuromuscular problem should be considered – such as residual neuromuscular blockade or a dense epidural block that paralyses the intercostal muscles. One also sees this pattern in patients with low physiologic reserve, the malnourished and the critically ill. In patients that have undergone thoracic surgery or retroperitoneal surgery, a high clinical suspicion for pneumothorax should be considered. This is characterized by hypoxemia, unilateral breaths sounds, and, in severe cases, hypotension.

Rapid shallow breathing with hypoxemia is caused by ventilation perfusion mismatch. This is usually caused by retained secretions and/or atelectasis. This most commonly occurs in patients that have undergone abdominal surgery, are morbidly obese or have been positioned intraoperatively in the Trendelenberg position.

Pulmonary embolism should be suspected in patients that have undergone pelvic or hip surgery with rapid shallow breathing and hypoxemia, associated with tachycardia and hypotension.

An obstructed breathing pattern is suggestive of upper or middle airway pathology. The problem is caused by central loss of pharyngeal tone, and soft tissue obstruction (associated with depressed level of consciousness and anesthesia) or mechanical obstruction to the airway, above, at the level of or below the glottis. Classically the patient has nasal flaring, supraclavicular or intercostal retraction, and a see-saw chest movement: the chest moves inwards as the diaphragm descends. The patient may have inspiratory stridor (supraglottic obstruction), expiratory stridor (glottic or subglottic obstruction) or expiratory wheeze (bronchospasm). Typically hypoxemia is a late complication of airway obstruction. This is important as hypoxia may be rapidly followed by bradycardia and asystole.

4. Solve or resolve the problem

This patient has many risk factors for acute respiratory distress. Does he have ventilatory failure? Quite possibly – he may be narcosed from excessive interoperative opioids. He may be hypoventilating due to splinting (upper abdominal pain due to surgical incision) or persistent partial neuromuscular blockade. He may have upper airway obstruction, due to loss of pharyngeal tone, obstruction with a bite block, laryngeal edema or laryngospasm. He may have severe bronchospasm, and inhaled foreign object (such as a tooth) obstructing a major bronchus, or the presence of blood or gastric contents aspirated from the upper airway. He may have lower airway collapse due to hypoventilation and or absorption atelectasis, diffusion hypoxia (due to oxygen being displaced by nitrous oxide in the alveoli) or alveolar fluid, due to excessive intravenous administration.

Working the problem:

Step 1: Is this failure to oxygenate or failure to ventilate?

The patient has rapid shallow breathing with hypoxemia – this is failure to oxygenate, it may be secondary to peripheral ventilatory failure, or primary to V/Q mismatch.

Step 2: Is this peripheral ventilatory failure or primary V/Q mismatch?

The patient has bilateral air entry into the upper segments of the lungs, with little air entry into the bases. This is primary V/Q mismatch secondary to atelectasis. The patient has an intra-pulmonary shunt, evidenced by the lack of responsiveness to oxygen therapy.

Step 3: How is the diagnosis confirmed?

The diagnosis may be accepted, clinically (there is sufficient clinical suspicion in this case) or confirmed by chest x-ray and arterial blood gas sampling.

Step 4: What is the initial management of this patient?

The patient should nursed in the upright or seated position – the effect of gravity is to recruit lung tissue and increase functional residual capacity. The patient should be encouraged to cough, to mobilize secretions. Consideration should be given to devices that assist in lung recruitment such as incentive spirometry or the use of non-invasive positive pressure ventilation. If the problem worsens or fails to resolve, the patient should be re-intubated and lung recruitment achieved using an ICU grade mechanical ventilator.

5. Conclusions

  1. The assessment of the patient with acute respiratory distress involves taking a history, examining the patient and quantifying the degree of respiratory injury.
  2. This involves determining whether the problem is failure to ventilate, failure to oxygenate or failure to maintain the airway.
  3. Failure to maintain the airway leads to failure of gas flow and ultimately hypoxemia and hypercarbia. The problem is either central loss of airway patency or mechanical airway obstruction.
  4. Failure to oxygenate is caused by ventilation perfusion mismatch: the patient typically has a rapid shallow breathing pattern.
  5. Failure to ventilate is caused by a problem in the central nervous system or a problem with the thoracic pump: the patient typically has a slow shallow breathing pattern.
  6. Failure to ventilate is an ominous sign.
  7. Look for an immediately reversible cause of failure to ventilate – such as narcosis, deep sedation or persistent neuromuscular blockade.
  8. In the absence of a reversible cause, positive pressure ventilation is required.


Figure 7: Failure to Oxygenate vs Failure to Ventilate

This article is entirely the work of Patrick J Neligan MA MB FCAI FJFICM. No part of this article or its illustrations may be reproduced without the author’s permission. Select illustrations were developed in conjunction with Maurizio Cereda MD. © PJN 2012

Agitation and Pain in the Recovery Room (tutorial)


A 43 year old male returns from the operating room following cholecystectomy. The operation had been originally planned using the laparoscopic approach. However it became necessary to convert to an open procedure. Intraoperatively the patient received fentanyl 300mic/g, propofol, vecuronium, oxygen and desflurane and cefazolin. At the end of surgery, neuromuscular blockade (sustained tetanus was demonstrated) was reversed, the patient opened his eyes and was extubated.

On arrival to the recovery room the patient is combative, thrashing around, incoherent, not obeying commands, attempting to remove has urinary catheter. His pulse rate is 120 beats per minute, blood pressure 170/100, temperature 37.0 degrees Celcius and his pulse oximeter is reading an SpO2 of 99%.

1. Identify the problem

What is the mechanism of injury and what are the treatment options?

This patient is agitated: the most common cause of postoperative agitation is pain. Pain is a neurohormonal and emotional response to a noxious stimulus, in this case surgical injury. Pain is the “fifth vital sign.”

Pain is known to worsen perioperative outcomes: it results in – increased protein catabolism – thereby reducing physiologic reserve, retention of salt and water, impaired wound healing, prolonged recumbent times (resulting in increased risk of deep venous thrombosis), and significant suffering and dissatisfaction on the part of the patient. Elevated adrenergic activity results in increased oxygen demand and may precipitate myocardial ischemia. In patients, such as in this case, that undergo upper abdominal surgery, the splinting effect of pain results in impaired coughing and lung derecruitment and increased risk of pulmonary complications including nosocomial pneumonia.

One of the major roles of perioperative clinicians is to minimize patient suffering. Patients universally report dissatisfaction with perioperative pain management.1 Modern approaches to preventing suffering in perioperative patients include a multimodal approach to pain, postoperative nausea and vomiting, anxiety, agitation and delirium.2-5

2. Understand the problem

What is pain (understanding the mechanisms)?

Table 1.  Inflammatory Mediators that amplify the pain response
Norepinephrine Nerve endings & circulating
Epinephrine Circulating
Substance P Nerve endings
Glutamate Nerve endings
Bradykinin Plasma kininogen
Histamine Platelets, mast cells
Hydrogen Ions (acidity) Ischemia / Cell Damage
Protaglandins Arachidonic acid / damaged cells
Interleukins Mast Cells
Tumor necrosis factor alpha Mast Cells

Surgical incision is associated with tissue injury and release of inflammatory mediators, development of local edema and activation of nocioceptors. These are nerve endings of myelinated (A-delta) and unmyelinated (C) afferent nerve fibres that respond to noxious thermal, mechanical, or chemical stimulation. A-delta fibres are mechanothermal while the C fibres are polymodal.

When nociceptors are activated, a series of neurohormonal reflexes are activated, and a painful sensation is elicited.6 In the awake patient, this is apparent by an adverse emotional response, a sensation of “unpleasantness”. In a sedated patient this may result in hyperadrenergic activity, agitation or aggressiveness.

Figure 1: Pain Pathways

1. The nocioceptive response is activated at the level of the surgical incision; 2. release of inflammatory cytokines and vasodilator metabolites; 3 transmission of nocioceptor impulses along afferent A-delta and C fibers; 4. integration and amplification in the spinal cord – c”windup”; 5 transfer of impulses from doral horns to thalamus and post-central gyrus; 6. activation of hypothalmo-pituitary adrenal axis; 7 release of cortisol, epinephrine and norepinephrine; 8 central and peripheral sensitization .

Normally, there is a relatively high threshold for activating nocioceptors. However, tissue injury alters the activity of these neurones, due to the  local production of inflammatory mediators (an “inflammatory soup” table 1). These include substance P, glutamate, bradykinin, histamine and arachadonic acid metabolites, such as prostaglandins. Their impact is twofold, to directly activate nocioceptors, and to reduce the firing threshold of these receptors.7 This is traditionally known as peripheral sensitization: lower stimuli than usual result in pain sensation. This is amplified in part by the systemic production of catecholamines secondary to activation of the hypothalmo-pituitary-adrenal axis. Moreover, epinephrine and norepinephrine induce a state of anxiety and diaphoresis that worsens the emotional response (figure 1). In addition, tissue trauma activates inflammation, and inflammation causes pain. Inflammation causes pain through the up-regulation of stimulated nociceptors and the recruitment of nonstimulated or dormant receptors.8 Proinflammatory mediatiors such as interferons, tumor necrosis factor alpha, interleukin-1 and interleukin 6 decrease the threshold for impulse generation and increase the intensity of the nocioceptive response.7 A patient emerging from anesthesia with elevated levels of stress hormones (cortisol and catecholamines) that is experiencing significant pain, will frequently become agitated and inappropriate, as in this clinical scenario.

Nocioceptor activation results in all-or-nothing depolarization of the afferent nerve. Painful impulses are transmitted to the dorsal horn spinal cord and subsequently to the thalamus and the post central gyrus.  In the spinal cord central sensitization may occur.9 A sufficiently strong stimulus may change the interpretation of painful impulses and subsequent stimuli are amplified. An area of hyperalgesia, composed of undamaged tissue, may appear adjacent to the injured site.10 This is due to “windup”, which results from repetitive C-fiber stimulation, mediated by glutamate via n methyl d aspartate (NMDA) receptors.11

Second order neurones synapse at the level of the spinal cord and transmit pain signals to the brain. Two predominant types of second order neurones have been identified: wide dynamic range (WDR) neurones and nociceptive specific (NS) neurones. Nociceptive signals ascend in the spinothalamic and spinoreticular tracts. These fibres project to multiple sites in the brain stem and midbrain, including the brain stem autonomic regulatory sites, hypothalmus and thalmus.

The body does have a pain regulating system that attenuates the response. This is modulated by a variety of neurotransmitters and inhibitory interneurones, that utilize endogenous encephalins and endophins and gamma aminobutyric acid (GABA). The binding of these endogenous opioids to central and peripheral receptors results in reduced presynaptic release of neurotransmitters, in particular substance P, and curtailed nocioceptor response.7



Opioids remain the mainstay of treatment for postoperative analgesia. Opioids exert their effects by binding to an array of receptors (“opioid receptors” μ, κ and δ) that exist in the central and peripheral nervous system and gastrointestinal tract. This results in analgesia and an array of characteristic side effects (table 2). In addition, opioids may have anti-inflammatory and immunomodulatory effects.7 A variety of naturally occurring, synthetic and semi-synthetic opioid agents are available for therapeutic use. These include full μ receptor agonists, partial agonists and agonists/antagonists (table 3). The choice of agent is dependent on the practice patterns of the clinician The majority of us use limited selection of full opioid receptor agonists, including morphine, hydromorphone, fentanyl, oxycodone, meperidine and methadone. Tramadol and codeine are weak receptor agonists.

Table 2: Side effects of Opioids
Nausea and Vomiting
Respiratory Depression
Urinary retention

Physicochemical Properties of opioids

There are two physiochemical properties of opioids that determine their pharmacologic action (table 4): degree of ionization and lipid solubility.  Opioids are weak bases. When dissolved in solution, they are dissociated into protonated and free-base fractions, with the relative proportions depending on the pH and pKa. The more unionized the agent, the more rapid its onset of action (table 3): hence alfentanil, which is 80% unionized (it has a pKa of 6.1) and remifentanil which is 70% unionized (pKa 7.1,) have more rapid onset of action than fentanyl (<10% unionized, pKa 8.4).

Lipid solubility is determined by the chemical structure of the agent. The more lipid soluble the agent the more easily the agent passes thru the blood brain barrier to the site of action. This also impacts onset of action: hence fentanyl has a more rapid onset of action than sufentanil which is more rapid thanmorphine or hydromorphone. Lipid solubility also impacts the volume of distribution of the agent: the higher the lipid co-efficient, the greater the amount of the drug sequestered in fat stores in the body. This is important when opioids are used as continuous infusions, resulting in a complex pharmacologic process known as “context sensitive half time.”

After intravenous injection, arterial plasma concentrations of opioids rise to a peak within one circulation time. Thereafter, they exhibit a rapid redistribution phase and a slower elimination phase typical of drugs whose pharmacokinetics are described by multi-compartmental models. Drugs that are more lipid soluble, such as fentanyl and sufentanil, redistribute extensively to fat, including non receptor fatty tissue in the brain. Alfentanil and remifentanil, agents that are not lipid soluble, have low volume of distribution and are rapidly cleared from plasma. Morphine, hydromorphone and meperidine have relatively low lipid solubility and are extensively metabolized by the liver. They have relatively long duration of action. Fentanyl and similar agents are also extensively cleared by the lungs.

Table 3: Opioid Agents available of Postoperative Analgesia


Dose im/iv

Oral Dose

Morphine 10mg equal to:

Onset (min) iv

Peak Effect (min)








10-20 min







5 hr


1-4 mg

1 mg

2 mg



3-4 hr


103 mg

200 mg

130 mg



3-4 hr




10 mg



3-4 hr


100 mg


125 mg



1 hr


2 mg


1.3 mg



30-60 min


2 mg

2-3 mg

2.3 mg



6-8 hr


50-100 mg


75 mg

1- 2


2-4 hr


2.5-10 mg

2.5-10 mg

10 mg



4-6 hr


10 mg

30-60 mg

10 mg



4 hr


10 mg


12 mg



4-6 hr



5 mg

10 mg

15-30 (PO)


4 hr


1 mg





4-6 hr


30 mg

50 mg

60 mg



3-4 hr



200 mg

200 mg

15-30 (PO)


4 hr


20 mg


12.5 mg



30-45 min



Morphine, a component of opium, has been used for analgesia and anxiolysis for millennia. If was first purified by Serturner, a German pharmacist, in 1803. He called this alkaloid “Morphia” after Morpheus, the Greek God of Dreams. Morphine is a phenanthrene opioid receptor agonist that exerts its major effects on the CNS and gastrointestinal tract. It is the prototype opioid analgesic agent, against which all other agents are compared. The majority of healthcare professionals are familiar with this drug in terms of its clinical effects, dosing and complications. This imparts a significant degree of safety; as a result I recommend morphine as the first line analgesic agent in PACU.

Following injection the onset of analgesic effect of morphine is 5 minutes with a peak effect at 20 minutes. Morphine is predominantly unionized (pKa 8.0) and has low lipid solubility: penetration into the brain is consequently relatively slow (table 4). Patients experience mild sedation prior to analgesia. This makes morphine an ideal analgesic agent for patients that are agitated and in pain, such as in this scenario, and patients requiring mild sedation for mechanical ventilation in the PACU or ICU. Conversely, the neurologic assessment of patients with brain injuries of following neurosurgery may be clouded by this effect.

Single boluses of morphine may be ineffective to establish adequate analgesia. Aggressive “loading” with the drug, to break the cycle of pain, may be required. This requires careful titration to analgesic and sedative response (figure 2).

Table 4 :  Physicochemical and pharmacokinetic data of commonly used opioid agonists
  Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil
pKa 8.0 8.5 8.4 8.0 6.5 7.1
% Un-ionized at pH 7.4 23 <10 <10 20 90 67
Partition Co-efficient 1 32 955 1727 129 16
% Bound to plasma protein 20–40 39 84 93 92 80?
Elimination half time (hours) 1.7-3.3 3.0-5.0 3.0-6.6 2.2-4.6 1.4-1.5 0.17-0.33

Morphine is known to have a direct histamine releasing effect. While the clinical implications of this are generally overstated, transient vasodilatation and hypotension may result. This is an unlikely problem in hyperadrenergic postoperative patients complaining of pain, but may be an issue in patients under general anesthesia or who are receiving concomitant propofol infusions. Morphine may cause euphoria. It alters the perception of pain: the patient knows that he/she is in pain, but is not bothered by it.

Figure 2: Effect of administration recurrent boluses of morphine on pain, and sedation in a typical postoperative patient in PACU. VAS = visual analog score; RASS = Richmond agitation sedation scale.

Morphine has an important side effect profile (table 2): it is a direct respiratory depressant, and acts by reducing the respiratory center’s responsiveness to carbon dioxide. Morphine induces nausea and vomiting by an effect on the chemoreceptor trigger zone. It induces miosis (pupillary constriction), causes constipation, may cause urinary retention and causes cutaneous vasodilatation. Morphine is a potent anti-tussive agent; again this may be beneficial in mechanically ventilated patients. Morphine is principally metabolized by conjugation in the liver, to morphine 3-glucuronide (M3G), which is inactive and  morphine 6-glucuronide (M6G), which is highly potent. There is also some extrahepatic metabolism in the kidney. Hence care should be taken when morphine is administered to patients with significant renal impairment, as delayed respiratory depression may follow.


Hydromorphone is structurally very similar to morphine. It differs from morphine by the presence of a 6-keto group and the hydrogenation of the double bond at the 7-8 position of the molecule.12 It principally acts at µ receptors, and thus shares a similar side effect profile. Hydromorphone is slightly more lipid soluble than morphine, and has a slightly quicker onset of action; its peak effect is at 20 minutes. Hydromorphone is less sedating than morphine and does not have active metabolites (although it is metabolized by the liver and metabolites accumulate in renal failure). Hydromorphone is widely used for patient controlled analgesia and for intravenous analgesia in the ICU. The major limitation of using hydromorphone is confusion regarding the appropriate bolus dose. Hydromorphone is roughly 7.5 times more potent than morphine; as a result one is more likely to encounter accidental (due to prescription error) overdose with this agent.


Fentanyl, alfentanil, sufentanil and remifentanil are semi synthetic opioids that have rapid onset and relatively short duration of action. Only fentanyl is routinely used for postoperative analgesia. It may be administered intravenously as bolus or infusion, transdermally through a patch or novel transcutaneous delivery systems, transorally (fentanyl “lollipop”), intrathecally or epidurally.13

Fentanyl has relatively rapid onset of action (1-2 minutes peak effect 5 mins) and short duration of action (20 minutes). However its therapeutic window is relatively narrow. When fentanyl is administered in low to moderate dose (1-5 mic/kg) intraoperatively, there may be little or no residual drug effect by the time the patient arrives in PACU. The patient may experience severe pain.

Fentanyl is highly lipophilic and redistributes to fat stores in the body; this may result in significant accumulation if given in high dosage. Its context sensitive half time is relatively long if administered by infusion. The complex pharmacology of fentanyl limits its effectiveness for perioperative analgesia. For prolonged effect, high dosage (5-15mic/kg) need to be administered, risking significant respiratory depression. Tachyphylaxis develops rapidly resulting in reduced effectiveness with escalating dose. This may result in significant problems such as ileus and urinary retention.

Although fentanyl can be used for analgesia in PACU, its effectiveness is limited to short episodes of analgesia, for example if coverage is required during a procedure – such as placement of a chest tube or epidural. It is not an effective agent for significant visceral pain unless given as an infusion or thru a PCA (patient controlled analgesia device). Transcutaneous fentanyl patches have slow onset of action and have no role in acute pain management. Newer products that utilize iontophoresis (a non-invasive method of propelling high concentrations of a charged substance transdermally using a small electrical charge), may make patient controlled fentanyl administration popular for ambulatory surgery.

Meperidine (Pethedine)

Meperidine is a semi-synthetic opioid structurally similar to fentanyl. Meperidine is one-tenth as potent as morphine. Meperidine is an effective analgesic and, in equianalgesic dosage, produces as much sedation, euphoria, respiratory depression and nausea and vomiting as morphine. Meperidine is significantly different pharmacologically to morphine, and has effects on a medley of receptors (see chapter on shivering). Of interest, meperidine has atropine like effects. The majority of opioids cause bradycardia, presumably by a direct or indirect action on the hypothalmo-pituitary-adrenal axis. Meperidine induces tachycardia. It also causes papillary dilatation. Meperidine has no anti-tussive effects. It has smooth muscle relaxing effects, and was used traditionally as analgesic for heptobiliary and ureteric surgery. However there is no evidence that this agent is superior to morphine in these situations. Meperidine causes less constipation and urinary retention than morphine. It has been used for generations for intramuscular analgesia in labor. The major current clinical use of meperidine is for treatment of postoperative anesthesia related shivering.

The major limitation of meperidine is its active metabolites: normeperidine (norpethidine) and meperidinic acid. Normeperidine accumulates, particularly in renal failure and may cause CNS stimulation (seizures or myoclonus)


Tramadol is an atypical opioid which is a centrally acting analgesic, used for treating mild to moderate pain. It is a synthetic agent, as a 4-phenyl-piperidine analogue of codeine.It can be administered orally or intravenously.

Tramadol is approximately 10% as potent as morphine, when given intravenously. It has effects on opioid, GABAergic, noradrenergic, NMDA (antagonism) and serotonergic receptors. Analgesia with tramadol is not fully reversed with naloxone although it has weak affinity for the μ-opioid receptor (approximately 1/6th that of morphine). The major issue with this agent is the serotonin modulating properties that may lead to interaction with selective serotonin reuptake inhibitors and result in serotonin syndrome (see chapter on malignant hyperpyrexia).

Tramadol causes significantly less respiratory depression and bowel dysfunction than conventional opioid analgesics.14 It does cause nausea and vomiting and may reduce seizure threshold.

Patient Controlled Analgesia

There is tremendous inter-patient variability in postoperative analgesic requirements. Coupled with greater demands on, and reduced availability of, nurses on postoperative wards, patient controlled analgesia has emerged as the gold standard delivery system for postoperative pain relief.15 Patients prefer PCA to nurse administered analgesia.16 Dolin and colleagues17 collected pooled postoperative pain scores from 165 publications and concluded that the mean incidence of moderate to severe pain was 67.2% and that of severe pain 29.1% for intramuscular opioids. The corresponding values were 35.8% and 10.4% for PCA, and 20.9% and 7.8% for epidural analgesia, respectively. The superiority of epidural analgesia has been confirmed by other investigators.18 Nonetheless, PCA, compared with conventional opioid treatment, improves analgesia and decreases the risk of pulmonary complications.19 In a large meta-analysis of fifty-five studies with 2023 patients receiving PCA and 1838 patients assigned to a control (parenteral ‘as-needed’ analgesia), PCA provided better pain control and greater patient satisfaction.20 Patients using PCA consumed higher amounts of opioids than the controls and had a higher incidence of pruritus (itching) but had a similar incidence of other adverse effects. There was no difference in the length of hospital stay.

Surprisingly, these results were not seen in many studies. This probably relates to the tremendous variability in settings applied to PCA devices: bolus doses, lockout, background infusions, opioid agents used etc.21 PCA strategy should be titrated to patient requirements. The best available evidence suggests that the optimal bolus dose of morphine is 1mg.22 Initial IV-PCA bolus doses of other drugs that are commonly used for opioid-naive patients are hydromorphone, 0.2 mg; fentanyl, 20 to 40 μg.21 The lockout interval is used to limit the frequency of demands made by the patient within a certain time. Lockout periods between 5 and 10 minutes are commonly prescribed. If analgesia is inadequate with a certain lockout period, it is more effective to increase the bolus dose rather than reducing the lockout.23 The use of a background infusion with IV-PCA, in addition to bolus doses on demand, is targeted at improving patient comfort and sleep: the expectation is that the patient will not awaken in pain. However, studies report no benefit to pain relief or sleep and no decrease in the number of demands made but a marked increase in the risk of respiratory depression.21 Background infusions should be limited to use in chronic opioid users.

Multimodal Analgesia

The concept of multimodal analgesia is based on the observation that pain is a multifactorial phenomenon – amplified and modulated at different sites both peripherally and centrally, and is therefore not amenable to control by opioid monotherapy alone.2;4;5

Figure 3: Multimodal Analgesia: a balanced approach to analgesia – different agents are combined to reduce pain transmission at different sites, targeting local nerves and neurotransmitters, the CNS and the neuroendocrine system.

The multimodal approach to perioperative pain management involves attenuating nociceptive activity at many different levels (Figure 3), including:

  • Reducing nocioception output at the surgical site, by superficial and deep wound infiltration.
  • Treating and preventing peripheral inflammation using nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Blocking afferent nerve activity by regional blockade using local anesthetics with or without other agents (opioids, tramadol, and ketamine). This blockade may be involve peripheral nerves (inguinal field block) neural plexuses (brachial or lumbar plexus block) or  spinal level (subarachnoid or epidural block)
  • Modulating central pain processes at the level of the brain or spinal cord (e.g., opioids, tramadol, NMDA antagonists, alpha-agonists). Some agents, such as opioids, have been shown to work at a number of levels (peripheral, spinal, cerebral).
  • Reducing adrenergic activity by direct or indirect actions using opioids or alpha-2 adrenoceptor agonists.

Wound infiltration with local anesthetic

Patients recurrently complain of pain at the site of superficial injury, i.e. at the skin incision site. Local anesthetic infiltration of the surgical site may reduce this.  A number of approaches have been shown reduce postoperative analgesia requirements including: infiltration into the subfacial parietal peritoneum, subcutaneous infiltration and field block, intraarticular injection, drains lavage etc.    Wound infiltration is a safe, simple, effective and under-utilized postoperative analgesic technique.

Non Steroidal Anti-inflammatory Agents (NSAIDS).

Non steroidal anti-inflammatory agents (NSAIDS) have been used for some time in ambulatory surgery to reduce the dose of opioid required for pain relief, with the potential for less nausea, vomiting and sedation. NSAIDS act peripherally to inhibit the cyclo-oxygensase enzymes responsible for production of pro-inflammatory mediators at the site of injury. The major therapeutic limitation of using these agents is the delay between application and onset time, because of peripheral action, as compared with opioids.  In order to attain full efficacy, it is essential to give NSAIDS at induction or early during the procedure.  NSAIDS, whether COX-1 or COX-2 inhibitors, are equally efficacious in terms of pain relief but their clinical applications are limited by concerns relating to gastric bleeding, renal impairment and platelet dysfunction.2 In general NSAIDS should be avoided in patients that have undergone mucosal surgery (such as resection of the nasal mucosa), intracranial surgery, some spinal surgeries and operations in which a cross-clamp has been placed on the aorta (abdominal aortic aneurysm repair for example). In addition, patients with known renal dysfunction are at risk of acute renal failure, and NSAIDS should be withheld.

NSAIDS may be administered by a variety of routes including oral, intravenous, intramuscular, and rectal.  Agents routinely utilized in the operating room and PACU include ketoralac, diclofenac and tenoxicam. There is a considerable body of evidence supporting the use of NSAIDS as adjunct analgesic agents.2;8;24  For example, ketoralac 30mg has equipotent analgesic effect to morphine 10mg. Where possible patients should be administered NSAIDS in the operating room or PACU.

Regional anesthetic techniques

A multitude of different regional anesthetic techniques has been used for surgery. These are frequently combined with general anesthesia to ensure absence of pain in the postoperative period. For example, paravertebral block has emerged as an effective option for breast surgery in addition to general anesthesia.25 Combinations of ileoinguinal and ileohypogastric nerve blockade and caudal block, have been shown to significantly reduce postoperative pain in children and adults following inguinal hernia repair.26 The commonly used regional nerve blocks are featured in Table 5.

Table 5   Regional Blocks that may reduce Postoperative Pain
Block Type Indication
Upper-limb blocks:
Bier’s block Surgery to hand or wrist (e.g. Colles’ Fracture)
Digital Nerve Block Surgery to finger
Wrist Block: median, ulnar and radial nerves Surgery to hand
Elbow Block: median, ulnar and radial nerves Surgery to hand or wrist
Brachial Plexus Block:
Axillary Approach Surgery to hand, wrist or lower arm
Supra-calvicular Approach Surgery to hand, wrist, upper and lower arm
Interscalene Approach Surgery to upper limb and shoulder
Neuraxial Blocks:
Spinal Surgery to lower extremities
Epidural Surgery to lower extremities, abdomen, thorax
Caudal Surgery to perinuem (e.g. hemmoroidectomy)
Paravertebral Block Thoracic and abdominal surgery (e.g. breast surgery, herniorrhaphy).
Lower-limb Blocks:
Sciatic Nerve Block Surgery to lower limb
Obturator Nerve Block Surgery to lower limb
3-in-1 (Lumbar Plexus) Block Surgery to lower limb
Knee Block: common peroneal, tibeal & saphenous Surgery to lower leg
Ankle Block Surgery to foot
Truncal Blocks
Intercostal Blocks Thoracic surgery
Inguinal Field Blockade Surgery in lower abdomen (e.g. hernia repair)
Penile Block Surgery to penis (e.g. circumcision)

Alpha-2 receptor agonists.

The alpha2 -agonists clonidine and dexmedetomidine have been reported to provide effective analgesia following a variety surgical procedures and when given by oral, intrathecal and intravenous routes of administration.

In general, alpha 2 -agonists are best used as adjuncts with other analgesics to minimize the side effects of sedation and hypotension. Clonidine, when given orally as a premedication (5 mg/kg), reduces morphine PCA requirements by 37% and significantly reduces the incidence of nausea and vomiting.27 When added to local anaesthetics, clonidine has been shown to augment the effectiveness and duration of action of peripheral nerve blocks.28


Paracetamol is an agent commonly used in multimodal techniques, due to its wide availability and low side effect profile in therapeutic dosage. Oral and rectal acetaminophen, as an adjunct to opioids, reduces pain scores by 20% – 30%.29 It has analgesic and antipyretic, but not anti-inflammatory, activity. Although the mechanism of action of acetaminophen is poorly understood, it is believed to act by the inhibition of the COX-3 isoenzyme and subsequent reduced prostanoid release in the central nervous system. In addition, there is some suggestion that it acts on the opioidergic system and NMDA receptors. Acetaminophen is a weak analgesic agent and has little or no anti-inflammatory activity. Thus it has no role as monotherapy-analgesia following major surgery. Nevertheless, there is abundant evidence that acetaminophen significantly enhances analgesia when combined with opioids and NSAIDS. It has little or no impact on the gastrointestinal tract or kidney. However, in high dosage acetaminophen may cause irreversible liver damage. This agent is strongly recommended for balanced analgesia in perioperative patients.

3. Differential diagnosis / Work the problem

What is the differential diagnosis?

An agitated patient, emerging from anesthesia, is in pain until otherwise proven (figure 4). It is imperative to assess the patient’s respiratory status to ensure that he is oxygenating and ventilating as hypoxemia and hypercarbia may manifest as agitation. The patient’s agitation should also be assessed in terms of their total physical status: in general agitation plus tachycardia and hypertension suggests hyperadrenergic activity (stress), and agitation associated with bradycardia suggests increased vagal activity. This can result, for example, from distress associated with a full bladder.

Postoperative patients that are agitated and tachycardic may have partial neuromuscular blockade (chapter 4: hypertension and tachycardia). Other potential diagnoses include drug withdrawal (beta blockers, clonidine, alcohol, cocaine and amphetamines), drugs (atropine, neostigmine, naloxone or flumazenil) and pathologic processes (neurologic injury, electrolyte abnormalities and endocrinopathy). Neurologic injuries include ermergence delirium, stroke, intracranial bleed, raised intracranial pressure and transcranial herniation. Electrolyte abnormalities that may cause agitation include hypernatremia, hyponatremia, hypokalemia, hypophosphatemia, hypercalcemia and hypomagnesemia). Endocrinopathies that may cause agitation include thyrotoxicosis, diabetic ketoacidosis, hypoglycemia, pheochromocytoma and carcinoid syndrome.

Figure 4: Managing the Agitated Patient

Common things are common – once life threatening causes of agitation have been outruled, one must address pain.

The clinical assessment of pain, analgesia, anxiety and sedation require quantification, hence the use of scoring systems. The behavioral pain score was discussed in chapter 4; it allows the bedside clinician determine whether or not the sedated patient is in pain. In this scenario the patient is agitated, and the level of agitation should be assessed using an alternative system, such as the Richmond Agitation Sedation Scale (RASS table 6).30 This tool allows the clinician to assess whether the patient is agitated or sedated using a + (plus) score for agitation and a minus (-) score for sedation. It then allows for titration of sedative drugs. The scale scores the patient from -5 (comatose) to +4 (combative, as in this case).

Visual Analog Scale for Pain

 No Pain           Mild Pain             Moderate Pain              Severe  Pain                  Worst


0         1             2            3          4        5          6            7          8          9            10

Figure 5: Visual Analog Scale

Once the patient is co-operative, pain should be assessed using a visual analog scale (VAS figure 6).31;32 This is a 0-10 scoring system in which 0 is no pain and 10 is the worst pain the patient has ever experienced. The goal is to obtain a pain score of 3 or less or pain that is considered acceptable by the patient.33 Occasionally the patient may report a higher score than would be suspected by physiologic data, and the bedside nurse is required to make an objective decision about the need for further analgesia.

Table 6    Richmond Agitation Sedation Scale

Clinical Status


Combative (violent dangerous to staff)


Very agitated (pulling on or removing catheters)


Agitated (fighting ventilator)




Spontaneously alert calm and not agitated


Able to maintain eye contact >= 10 seconds


Able to maintain eye contact < 10 seconds


Eye opening but no eye contact


Eye opening or movement with physical or painful stimuli


Unresponsive to physical or painful stimuli (deeply comatose)


4. Solve or resolve the problem  

Step 1: Ensure that the airway is patent and that the patient is breathing spontaneously. Apply supplemental oxygen. Ensure that the patient has iv access and that intravenous fluid is running. Check the patient’s pulse and blood pressure. Position the patient in the semi-recumbent position.

Step 2: Score the patient’s agitation/pain using RASS and VAS

Step 3: Commence the opioid titration protocol (figure 6).34;35 The choice of agent, morphine or hydromorphone is determined by the clinician – if the patient is to receive a morphine PCA they should receive bolus morphine, a hydromorphone PCA – bolus hydromorphone etc. The dose should be adjusted for the patient’s weight.

Step 4: The goal of the opioid titration protocol is to aggressively treat pain by assessing the patient’s pain score,33 and to prevent oversedation by using the RASS score.

Step 5: If the patient remains agitated despite significant opioid administration, consideration should be given to anxiety and delirium. Delirium is defined as an acute disturbance of consciousness (reduced clarity of awareness of the environment) and cognition with reduced ability to focus, sustain or shift attention. The patient may be disorientated in time, place or person. If the patient is orientated, anxiety may be a problem, and this can be managed with judicious administration of midazolam 1-2mg iv. Anxiolytics should not be administered before analgesics in the agitated postoperative period unless the significant consideration has been given to pain as the etiology of the problem.

Step 6: If the patient is complaining of severe intractable pain, out of proportion to the injury and unresponsive to analgesia and anxiolysis, consideration should be given to an surgical problem. For example, in a patient that has had orthopedic surgery to the leg, severe pain may signal a compartment syndrome: the patient has ischemic pain. If a surgical cause had been discounted, consideration should be given to a regional anesthetic approach (epidural, brachial plexus catheter etc) or to the addition of ketamine to the PCA.

Step 7: If the patient becomes oversedated (RASS -3 or below) as a result of narcosis (associated with bradypnea), opioid administration should be discontinued until the RASS score is -2 or above. In extreme cases, where the patient is comatose and hypoventilating, naloxone should be administered in aliquots of 40mic/g, until the RASS is -2 or above. It is essential that the clinician consider alternative causes of coma, such as stroke, brain hemorrhage or intracranial hypertension).

Figure 6: Management of Patient in Pain or Agitated


  1. Pain is now considered the “fifth vital sign”.
  2. Postoperative patients that are agitated should be considered to be in pain until otherwise proven.
  3. Pain is a multisystem problem that manifests as an emotional response to a noxious stimulus. Pain starts at the nocioceptor and is amplified by local inflammatory mediators and spinal cord windup leading to central and peripheral sensitization. In addition, pain activates the hypothalmo-pituitary-adrenal axis leading to anxiety and diaphoresis.
  4. Pain should be managed by a multimodal approach that addressed the problem at different levels in the pain pathways.
  5. Opioid agents remain the mainstays of management of pain. Of these morphine and hydromorphone are the most popular and effective agents for managing visceral pain in PACU.
  6. Opioids should be titrated using an opioid titration protocol, that scores both pain and sedation.
  7. Anxiety, delirium and surgical problems may worsen pain, and should be addressed by the clinician.
  8. Pain that is unresponsive to aggressive and analgesic therapy should prompt the clinician to consider a surgical cause.

This PBLD was written by Patrick Neligan Version 1.3 September 2007



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 This Article Copyright Patrick Neligan MA MB FCAI DIBICM 2007-2012. Neither text nor illustrations are to be used without permission.