The Agitated (NIPPV) Patient

My experience with non-invasive positive pressure ventilation (NIPPV) is occasionally made up of the following issues:
1. Mask fitting properly (we always guess a size too big).
2. Increased 02 Consumption (@bryanwinchell has a wicked app for this).
3. Comfort level of the patient 
There is limited literature to support the ideal agent to calm down a patient who appears anxious during NIPPV. This literature becomes even more scarce if you do not carry dexmedetomidine (most of us?).
Midazolam vs. Dex
A randomized double-blinded trial comparing midazolam with dexmedetomidine's ability to reduce anxiety during NIPPV (Senoglu, 2010), found both agents equally as effective. There were more dosing adjustments needed in the midazolam arm. I put together snap shots of particularly interesting findings of this study.
My Initial Thoughts
1. The dosing protocol for midazolam was 0.05mg/kg over ten minutes, followed by an infusion of 0.1mg/kg/hr. This would put me at a 5mg dose (100kg). I will openly admit that I generally start lower than this for NIPPV induced anxiety (1-2 mg).
2. The PaC02 actually decreased as the respiratory rate decreased. This paradoxical effect is most likely due to improved tidal volumes and resolution of dead-space breathing. This is discussed by Sam and Chip in a recent TOTAL EM podcast here.
3. Net reduction in anxiety at one hour (transport range) was very similar between groups and within a safe range (2.2 vs 2.1, P0.023)
4. There was one patient that was not able to be relaxed by midazolam in this study. This confirms pre-existing anecdotes for occasional paradoxical delirium associated with benzodiazepines. 
What about Ketamine?
Generally I teach that if your analgesic dosing of ketamine appears to be having a sedation effect, you are getting close to the recreational and dangerous dosing zone.
(Graph By Sam Ireland)
The anxiolysis dosing literature for ketamine appears to be once again scarce and primarily focused on intra-nasal dosing for pediatrics. I would venture to say that if the patient was in pain from any vcause, and the anxiousness was from the pain, relief of the pain would logically remove the anxiety. I just do not see many patients on NIPPV in pain. If you are aware of any literature showing anxiolysis at the analgesic range, please send it to me. Wish I could go back to 1986 and evaluate a few more parameters.
Reduction in pain from low dose ketamine may be beneficial. I largely find that the pain comes from improperly positioned masks (tightening the mask on the head can have a paradoxical gap effect on the chin). 
The general lack of evidence and current understanding, pushes my clinical momentum away from ketamine for the time being. Josh Farkas mentions utilizing a dissociating dose of ketamine in the initial phases of NIPPV here. I can only see myself doing this as a tool to assist in pre-oxygenating a patient prior to intubation. In most EMS systems, dissociation will unfortunately fall as a contraindication to NIPPV. This can inherently lead to a case of GCS3K patients being intubated.
The secondary issue is when patients are coming down from the "disassociation ladder." Some will pass through the danger zone and need benzodiazepines to prevent an emergence reaction. (Deepa, 2015).
Haloperidol is an antipsychotic medication that works by inhibiting dopamine receptors in the brain. This may be a valid option, but the evidence is limited. I spent almost an hour searching for studies or case reports evaluating its use during NIPPV. I found a study done in Japan that looked at the use of several sedation agents during NIPPV to improve patient tolerance. Here are a few snap shots.
The study design is a little confusing initially. They separated the groups into cohorts that had "do not not intubate" orders and those that didn't. This is further separated into intermittent, bolus switched to continuous, and initially continuous dosing regimens. My particular interest was in the intermittent dosing as it pertains to what I generally see used in EMS. Haloperidol was the most common medication utilized in this group (87/120 or 73%). 
In the Non-DNI group the intermittent dosing regimen was associated with increased mortality (P0.37), total intubation (P0.94), and intubation due to agitation (P0.36). Due to the unbalanced enrollment in the "Non-DNI" group, these results were not statistically significant.  In the DNI group, intermittent dosing regimen was associated with lower mortality (P0.020), and two patients that needed to be discontinued from NIPPV due to agitation (P0.66).
The only statistically significant finding in this study was decreased mortality in the intermittent dosing regimen within the "DNI" group. This finding has a fragility index of two and the initial P value in this study was calculated utilizing a Chi-square without Yates correction. If two more people would have died in the intermittent group, the results would yield a P value just above 0.05.
There may be a role for fentanyl in a patient that has hyperventilation induced hypercapnia. Rapid and shallow ventilation can cause hypercapnia by either:
1. Only moving enough air to clear dead-space caused by anxiety (the long snorkel effect).
2. Not allowing full exhalation between breaths.
If caught early enough, and before total exhaustion takes place, opioids may have a role in normalizing breathing patterns. There appears to be some physicians that are already doing this, and prefer it over ketamine (Stemp, 2013).
So what do you do?
Due to an underwhelming amount of literature and lack of evidence, I believe this will be an area that remains locally anecdotal. My practice now is 0.025mg/kg of Midazolam. There are several articles that say to avoid benzodiazepines, yet the best literature we have shows them to be effective and safe (Senoglu, 2010). 
My mental flow looks something like this:
Although I have never used it in this scenario, I feel fentanyl may be a better option for the hyperventilating patient with hypercapnia. However the dosing for this remains anecdotal. 
Microgram - Is Flow Additive?
The Space Between (Interventions)
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