This document discusses the history and development of sedation use during non-invasive ventilation (NIV). It notes that early studies in the 1980s explored the use of NIV without discussion of sedation. Between 2007-2012, several studies began exploring the use of sedation with NIV in a protocolized manner using various agents like dexmedetomidine and midazolam. Larger trials found that routine early use of dexmedetomidine did not universally improve NIV tolerance. Overall, the document traces the limited data available on sedation during NIV and concludes that while it appears safe and feasible, more high-quality randomized controlled trials are still needed to establish best practices.

1. 9/15/2019 DR VIJAY K AGRAWAL 1
Dr. VIJAY K. AGRAWAL
MBBS, MD, FCCP, FCCS, IDCCM
DIRECTOR, CRITICAL CARE MEDICINE & ACADEMIC PROGRAMS
SENIOR CONSULTANT, RESPIRATORY MEDICINE
HEAD ITC/AHA BLS-ACLS COURSES & INFECTION CONTROL PROGRAM
METRO HEART INSTITUTE WITH MULTISPECILAITY, FARIDABAD
NIV AND SEDATION

2. Disclosure Statement of Financial Interest
I DO NOT have a financial
interest / arrangement or
affiliation with one or more
organizations that could be
perceived as a real or
apparent conflict of interest
in the context of the subject
of this presentation.

3. Till date knowledge- TIP OF ICEBURG
“An area with limited robust data to guide
the development of best practice”
and
“ Where local custom appears to exert a
strong influence on patterns of care”

4. First pioneering studies of noninvasive positive
pressure ventilation in critical care
- early & late 1980s
Smith RA, Kirby RR, Gooding JM, Civetta JM.
Continuous positive airway pressure (CPAP) by face mask.
Crit Care Med 1980; 8:483-85
First time publication on
CPAP used with non –
invasive method in
respiratory failureAbstract
The authors studied the use of CPAP by face mask in 44 patients with mild to moderate
acute respiratory insufficiency (mean PaO2/FIO2 = 171 +/- 42 (SD). All patients improved
their oxygenation (mean PaO2/FIO2 = 300 +/- 68 (SD) after the application of CPAP (mean
9 +/- 3 (SD) cm H2O). One patient developed a respiratory acidemia and was intubated.
No other significant complications or adverse side effects occurred. The authors conclude
that CPAP by face mask in a select group of patients will improve lung function and
arterial oxygenation without the use of tracheal intubation and mechanical ventilation.

5. • Naver L, Walter S, Glowinskij. Pulmonary fat embolism
treated by intermittent continuous positive airway pressure
given by face mask. Br Moo J (1980); 14:1413-14
First time - PEEP in
mechanical
ventilation was
used in 1969
First time Intermittent
CPAP without
mechanical ventilation
was used in 1980

6. Hurst JM, DeHaven CB, Branson RD.
Use of CPAP mask as the sole mode of ventilatory support in
trauma patients with mild to moderate respiratory insufficiency
Trauma 1985; 25: 1065-68
J Trauma. 1985 Nov;25(11):1065-8.
Use of CPAP mask as the sole mode of ventilatory support in trauma patients with
mild to moderate respiratory insufficiency.
Hurst JM, DeHaven CB, Branson RD.
Abstract
33 trauma patients presenting with hypoxemia and normo- or hypocarbia were
treated with continuous positive airway pressure (CPAP) via a snug-fitting face mask.
All patients had demonstrated continued hypoxemia despite supplemental oxygen
administration before institution of CPAP therapy as the primary mode of ventilatory
support. Therapeutic end-point of PaO2/FIO2 greater than 300 was achieved in 32 of
33 patients. Duration of CPAP treatment was 28 +/- 19 hours. Two patients (6%)
required intubation, but neither for elevation in PaCO2.
Conclusion –
CPAP mask appears an effective means of support for mild to
moderate post-traumatic respiratory insufficiency.

7. In 1989, first time face mask with ventilator in
COPD and hypercapnia patients

8. 1990 – Inspiratory assist device or IPPV was
used with face mask in COPD.
Total 11 patients
Only 1 intubated

9. 1991- first time CPAP in cardiogenic
pulmonary oedema

10. 1995 – first time protocolized group comparison
in COPD patients with or without NIV

11. 1998 - First time discussion on sedation during NIV use
started
1998
• Multicenter, randomized trial
• Intervention: A T-piece weaning trial was attempted 48 hours after intubation. If this
failed, two methods of weaning were compared: 1) extubation and application of
noninvasive pressure support ventilation by face mask and 2) invasive pressure
support ventilation by an endotracheal tube.
• Some minor side effects were recorded in the noninvasive
ventilation group- cutaneous irritation of the nose, nose
abrasion, gastric distention, and most patients reported poor
sleep, especially in the first few days.

12. Mask intolerance or inadequate patient cooperation
led to intubation in 9% of patients with Acute
Respiratory Failure.
Lancet 2000; 356: 2126–32

13. JAMA. 2000 Nov 8;284(18):2352-60
Treatment of acute hypoxemic non-hypercapnic respiratory
insufficiency with continuous positive airway pressure
delivered by a face mask: A randomized controlled trial
OBJECTIVE:
To compare the physiologic effects and the clinical efficacy of CPAP vs standard
oxygen therapy in patients with acute hypoxemic, non-hypercapnic respiratory
insufficiency.
Randomized, concealed, and unblinded trial of 123 consecutive adult patients
CONCLUSION:
In this study, despite early physiologic improvement, CPAP neither reduced
the need for intubation nor improved outcomes in patients with acute
hypoxemic, non-hypercapnic respiratory insufficiency primarily due to acute
lung injury.
Delclaux et al. found up to 14% of patients in ARF were
unable to tolerate face-mask ventilation

14. Authors reported that
when NIV was discontinued early, the reason for
discontinuation was the patients’ refusal to
continue in 22% of cases due to intolerance.
Am J Respir Crit Care Med Vol 163. pp 874–880, 2001
Study in 42 ICUs, over three week period

15. Delirium and agitation are serious complications and even
if it is indicated, NIV sometimes fails under these
conditions, requiring endotracheal intubation.
2002

16. Since 1980 –till 1999
Non-invasive positive-pressure ventilation with a face
mask or mouth seal was effective in supporting
ventilation for years in various diseases
Discussed complications were aerophagia,
dehydration of the oropharynx, bite deformities from
the mouth seal or intolerance
But………
No one discussed about possible role of sedations in
agitated patients or intolerance of NIV

17. 1999
2007
2010
2008
2009
2010
2010
2012
Between 2007 to 2012
few studies on sedation with NIV in
protocolized manner and trial of various
agents
First time
sedation
with NIV

18. Hill et
al.2000
First time sedation protocols were used /
but abstract only study
Patients received neuromuscular blocking
drugs and sedatives in immediately preceding
phase of invasive ventilation. Use of sedation
during NIV not clear
2009
2004
Vaschetto et al. 2012 [8] / 20 Hypoxemic respiratory failure patients / invasive mechanical
ventilation for at least 48 h before NIV / Helmet NIV
Sedation reportedly used during NIV but apparently not protocolized or defined.
Continuous sedation during NIV reported
21 patients

19. Hill et
al.2000 First time sedation protocols were used / but abstract only study
Patients received sedatives in immediately
preceding phase of invasive ventilation.
Use of sedation protocol during NIV was not
clear
2009
2004
Vaschetto et al. 2012 [8] / 20 Hypoxemic respiratory failure patients / invasive mechanical
ventilation for at least 48 h before NIV / Helmet NIV
Sedation reportedly used during NIV but apparently not protocolized or defined.
Continuous sedation during NIV reported

20. Hill et
al.2000 First time sedation protocols were used / but abstract only study
Patients received sedatives in immediately
preceding phase of invasive ventilation.
Use of sedation protocol during NIV not clear
2009
2004
Vaschetto et al. 2012 [8] / 20 Hypoxemic respiratory failure patients / invasive mechanical
ventilation for at least 48 h before NIV / Helmet NIV
Sedation reportedly used during NIV but apparently not
protocolized or defined. Continuous sedation during NIV reported

21. 1999
2007
2010
2008
2009
2010
2010
2012
Between 2007 to 2012
few studies on sedation with NIV in
protocolized manner and trial of various
agents

22. Crit Care Med 2007; 35:2298–2302
• Physician members
of ACCP critical care
network (n = 2,656)
and the ERS assembly
of critical care (n =
339) surveyed.
• 790 of 2,985 (27%)
physicians
responded.

23. First-choice sedation regimens
Crit Care Med 2007; 35:2298–2302

24. Frequency of use of NIV in
patients with ARF
Crit Care Med 2007; 35:2298–2302

25. CONCLUSIONS
“Sedation appears to be used infrequently for ARF
patients treated with NPPV, and current sedation
practices are heterogeneous and mainly determined
by clinical experience because of the lack of an
evidence base.”
Crit Care Med 2007; 35:2298–2302

26. Anesth Analg. 2008 Jul;107(1):167-70.
First time dexmedetomidine was used with NIV

27. Curr Ther Res Clin Exp. 2010 Jun;71(3):141-53
• The first randomized controlled trial compared 24-h infusions of
dexmedetomidine and midazolam in 40 uncooperative patients
receiving NIV for ARF due to acute exacerbations of COPD
Conclusion-
• Though no patient experienced NIV failure during the study period,
compared to midazolam, dexmedetomidine required fewer
dosing adjustments to maintain adequate sedation
• This study, however, considers only the first 24 h of NIV and does not
provide valuable information on any outcome variable.

28. Assess the feasibility of remifentanil-based sedation in ARF
patients refusing to continue NIV for intolerance
Started sedation remifentanil (0.025 mcg/kg/min), rate increased
by 0.01 mcg/kg/min every minute to a max of 0.12 mcg /kg/min
to obtain patient comfort (RAS 2 to 3)
Intensive Care Med (2010) 36:2060–2065

29. Intensive Care Med (2010) 36:2060–2065
Conclusion:- This preliminary study suggest
that the use of remifentanil-based sedation is
feasible and safe

30. NIV failure due to discomfort, agitation and/or refusal to continue NIV were
included.
Sedated by TCI of propofol during NIV sessions.
NIV under TCI of propofol significantly improved ABG
In a selected population, TCI of propofol can facilitate
acceptance of NIV & propofol seems to be safe and effective
for the treatment

31. (Intern Med 51: 2299-2305, 2012)
• Randomized controlled CHINA study
• Enrolled 62 hypoxemic patients with acute pulmonary edema
failing NIV because of discomfort leading the patients to refuse
continuing NIV

32. Observations of study-
• Except that bradycardia occurred more with dexmedetomidine, there
were no serious adverse events, and none of the patients interrupted
the study protocol.
• The main outcome variable was the rate of failure, i.e., endotracheal
intubation, which was overall 32 %.
• In the dexmedetomidine group of patients NIV failure was lower (21
%) than in the midazolam group (45 %)
• In addition, dexmedetomidine led to a more desired level of awake
sedation, shortened the duration of mechanical ventilation, the length
of ICU stay, and further reduced the prevalence of nosocomial
infection.

33. First expert opinion on topic
Key messages
The current limited data available suggest that sedation during NIV
is safe and feasible.
More widespread application should await the results of randomized
clinical trials.

34. CHEST 2014; 145(6):1204 –1212

36. CHEST 2014; 145(6):1204 –1212
Conclusion of study
Routine early use of low-dose Dexmed during NIV does
not improve overall tolerance of NIV, but may have
beneficial effects for who are initially less tolerant.
Dexmed appears to be safe, although was associated
with greater occurrence of deep sedation.

37. The objective of this ancillary study was to estimate the effect of analgesic or
sedative drugs on the failure of NPPV.
Methods: Studied patients who received at least 2 h of NPPV as first-line therapy in a
prospective observational study carried out in 322 intensive care units from 30
countries. A marginal structural model (MSM) was used to analyze the association
between the use of analgesic or sedative drugs and NPPV failure (defined as need for
invasive mechanical ventilation).
Results: 842 patients were included in the analysis. Of these, 165 patients (19.6 %)
received analgesic or sedative drugs at some time during NPPV; 33 of them received
both.
Conclusions: Slightly less than 20 % of patients received analgesic or sedative
drugs during NPPV, with no apparent effect on outcome when used alone.
However, the simultaneous use of analgesics and sedatives may be
associated with failure of NPPV.
2015- global involvement

38. The study has limitations
• Do not know whether analgesics and/or sedatives were always given
with respect to the interface tolerance or also administered for
associated causes not strictly depending on NIV, such as agitation,
pain, dyspnea, or tachypnea unrelated to NIV.
• It was unclear whether analgesics and/or sedatives were administered
to prevent or treat NIV intolerance.
• It was uncertain for how long the patients underwent NIV before being
sedated.
• The study cannot differentiate among the route of administration
(IV/IM/SC/ORAL), type of drugs (short acting vs. long lasting),modality
of administration (continuous versus bolus), duration of sedatives
and/or analgesics administration,or specific protocols used.

39. 2015 – Europe
Analysis of available trials / papers..
Conclusion - Is sedation safe and beneficial in patients receiving NIV? Yes,
definitely.
The ideal indication for sedation during NIV is unknown but could be when
mask intolerance and/or lack of cooperation may lead the patient to refuse
ongoing NIV.
Thus, the objective is clearly to avoid intubation.
While awaiting further randomized controlled trials clarifying the role,
modalities, and indications, we believe it is wise to suggest the separate use of
sedative or analgesic agents to treat NIV intolerance due to discomfort.

40. 2015 - Japan
Conclusions: According to RASS scores, sedation during NIV in
proficient hospitals may be favorably used to potentially avoid NIV
failure in agitated patients, even in those having diseases with poor
evidence of the usefulness of NIV.
However, with continuous use, we must be aware of an increased
hypercapnic state and the possibility of increased mortality.
Of 3506 patients who received NIV, 120 (3.4 %) consecutive patients were analyzed
Retrospectively reviewed sedated patients who received NIV

41. 33(2015) 1720E 1-2
CASE REPORT
36 years male, severe asthma exacerbation, intolerance to NIV
IV ketamine 50 mg bolus , repeated every 5-10 minutes till total 300 mg.
Tolerated well and discharged

42. Potential other applications
of sedation during NIV

43. Clouzeau B, Bui HN, Guilhon E, Grenouillet-Delacre M, Leger MS, Saghi T et al.
Intensive Care Med 2011;37:1969-75.
Fiberoptic bronchoscopy under non-invasive ventilation and
propofol target-controlled infusion in hypoxemic patients
Trial has shown that bronchoscopy with BAL, under NIV and
TCI (target-controlled infusion) with propofol, is feasible and
safe in non-intubated patients with ARF. Patient discomfort was
reduced with no significant adverse effects.
But, performance of awake bronchoscopy in hypoxic sedated patients
should only be performed when practitioners skilled in airway management
and endotracheal intubation are present.
Requires further studies.

44. Ambrosino N, Guarracino F.
Eur Respir J. 2011;38:440-9
Unusual applications of noninvasive ventilation
• During trans esophageal echocardiography as well as in
interventional cardiology and respirology, NIV can reduce the
need for deep sedation or general anaesthesia and prevent
respiratory depression induced by deep sedation.
• Propofol infusion for sedation during anesthesia was used during application
of NIV in 23 patients undergoing repair of inguinal hernia under spinal
anesthesia. There were no adverse effects.
Ohmizo H, Morota T, Seki Y, Miki T, Iwama H. Combined spinal-propofol
anesthesia with noninvasive positive-pressure ventilation. J Anesth 2005;19:311-4.
• These findings suggest that the application of NIV in patients receiving
sedative infusion is clinically practicable during anesthesia.

45. Sedation with NIV
Recommendations
7. Sedation should only be used with close monitoring (Grade D).
8. Infused sedative/anxiolytic drugs should only be used in an HDU or ICU
setting (Grade D).
9. If intubation is not intended should NIV fail, then sedation/anxiolysis is
indicated for symptom control in the distressed or agitated patient (Grade D).
Good practice point
In the agitated/distressed and/or tachypnoeic individual on NIV, intravenous
morphine 2.5–5 mg (± benzodiazepine) may provide symptom relief and may
improve tolerance of NIV.
2016

46. NO meta-analysis
No clear guidelines
Need more studies
NIV AND SEDATION

47. Current perspective of sedation in NIV
• Significance of agitation, delirium and dyspnea during
respiratory failure needs proper address
• We as physicians are either indifferent to or unconcerned
about the general topic of sedation during NIV
• No single sedative agent currently available that fulfils the
criteria for an ideal agent

48. Indications of sedation with NIV
To minimize the requirement for endotracheal
intubation and to provide patient comfort (so as to
optimize the chances of success during NIV) in case
of intolerance , Delirium and agitation
But…
After considering other factors known to improve adaptation of the
patient to NIV including use of full-face mask, attention to air leaks
responsible of ineffective efforts during persistent insufflations etc…

49. Sedation goal
1. To maintain
a) Arousability
b) Respiratory drive
c) Cough reflex
d) Airway protection
2. Reduction of pain and agitation
3. Avoidance of exacerbating factors
4. Allowing the patient to easily
interact with the NIV

50. Monitoring during sedation
Tools available to ensure adequate levels of sedation
• Ramsay Sedation Scale (RSS)
• Sedation Agitation Scale
• Richmond Agitation-Sedation Scale (RASS)
• Bispectral Index (BIS)
Various pain scales
• Numeric Rating Scale
• Behavioral Pain Scale
• Critical Care Pain Observation Tool
• Nonverbal Pain Scale

51. Dexmedetomidine
• Centrally acting α2-adrenergic receptor agonist
• Metabolized hepatically
• Elimination half-life of 2 h
• Sedation, analgesia, and anxiolysis without adverse
effects on respiration
• Low risk for delirium
• Doses in the range of 0.2–0.7 μg/kg/h

52. Midazolam
• Sedative agents that act via the GABA A receptor
• Metabolized hepatically with renal clearance of
active metabolites, which can accumulate during
prolonged infusion
• Strongly associated with delirium

53. Remifentanil
• Ultra-short-acting agonist of the μ-opioid receptor
• Provides analgesia and sedation.
• Rapid offset even after prolonged infusion
• Does not accumulate
• Elimination via nonspecific blood and tissue esterases
• Depression of respiratory drive >0.05 μg/kg/min

54. Propofol
• Anesthetic agent that acts via the GABA- A receptor
• Sedation, anxiolysis, and amnesia without analgesia
• Primarily metabolized hepatically, with some extrahepatic
metabolism
• Has a dose- dependent duration of action
• Respiratory depression, hypotension, rarely PRIS

55. ketamine
• Phencyclidine derivative
• Short acting
• Is a dissociative anaesthetic (as it produces a cataleptic state in
which the patient appears to be awake but is detached from the
environment and is unresponsive to pain.)
• Ketamine is frequently described as a “unique drug” because
it has hypnotic, analgesic and amnesic effects – no other drug
used in clinical practice combines these three important
features.
• Rapid onset of action: 30 to 60 sec.
• Metabolism in liver
• Elimination half line time : 2-3 hours

56. Drug IV Bolus Dose Infusion Rate Onset to Peak Duration Sedation
target range
Propofol 0.03-0.15
mg/kg
5-80
mcg/kg/min
1-2 min < 20 min OAAS/S 3-4
Midazolam 1-6 mg 1-10 mg/hr 5-10 min 1.5-2 h RSS 2-3; RASS
2-4; BIS >85
Lorazepam 1-3 mg 1-5 mg/hr 15-20 min 2-4 hours
Dexmedetomi
dine
1 mcg/kg over
20 min (not
recommended
0.2-1.5
mcg/kg/hr
30 min 2-4 hours RSS 2-3; RASS
2-4; BIS >85
Remifentanil 0.5-1 mcg/kg
Infused over
>30 sec
0.025-
0.1 μg/kg/min
1-2 min RSS 2-3
Fentanyl 25-50 mcg 3 min 30-60 min
Ketamine 0.5-1 mg/kg 0.15 mg/kg/h 3 min
Shortness of Breath. 2013;2:35–43

57. PONV= postoperative nausea and vomiting PVD= preservation of ventilatory drive.
Larger numbers indicate a more satisfactory impact on the nominated
property.
Individual category scores and in particular scores shown in the ‘Total’ column are crude
summaries that should not be over-interpreted and which do not necessarily reflect the net
merits or demerits of particular agents in the circumstances of a particular patient.
Properties of sedative drug classes relevant to delivery of sedation in NIV
Haemody
namic
Stability
Analgesia Amnesia Anxiolysis P
V
D
Avoidance
of PONV
Promoti
on of
natural
sleep
Suitability
for use
after
extubation
Delirium
avoidanc
e
Total
Propofol 2 2 2 2 2 4 2 2 1 20
Midazolam 3 2 4 2 2 2 2 1 1 19
Opioids 4 4 1 2 1 1 1 2 1 20
Dexmedet
omidine
3 2 2 4 4 2 4 4 3 28
Ketamine 4 3 2 1 4 1 1 4 1 21

58. Summary /
Take home massage

59. • The use of sedation during NIV is part of a strategy designed to optimize the
use of NIV in selected patients at risk of failure of the technique and ensuing
intubation.
• Taken together, the results of available studies are encouraging
• Overall, the use of sedation during NIV appears feasible and safe.
• The ‘‘curative’’ use of sedation–analgesia, i.e., applied for treating discomfort
leading to NIV intolerance, seems to be able to avoid intubation in 55–70 % of
cases, while ensuring the desired level of awake sedation.
• By contrast, the ‘‘preventive’’ administration of sedation–analgesia, i.e., at
initiation of NIV to prevent discomfort leading to intolerance, has so far not
shown encouraging results .
• The use of a single sedative or analgesic drug should help to improve NIV
tolerance in the vast majority of patients, and in the case of failure of one
drug, the association of sedative and analgesic drugs is unable to further
improve NIV tolerance and may be deleterious

60. • No single sedative agent is currently available that fulfils the criteria for an
ideal agent
• Bbenzodiazepines should be avoided and dexmedetomidine could have the
most suitable overall profile
• Further studies are definitely needed to determine the ‘‘ideal’’ sedative or
analgesic drug to be used during NIV, as well as the ‘‘best’’ route and
modalities of administration.
• As frequent dose adjustments are required to apply sedation–analgesia during
NIV, a safe environment and close monitoring are necessary, which restricts its
use to the ICU setting.
• Finally, before considering sedation–analgesia to improve patient comfort, we
should always first consider the other factors known to improve NIV tolerance
and patient cooperation, such as the choice of the interface (type, size, and fit),
ventilator settings, control of air leaks, and containment of patient– ventilator
asynchrony.

61. THANKS