Effects of Obstructive Sleep Apnea Treatment On Opioid-Induced Respiratory Depression

Between 5 and 50 million patients with obstructive sleep apnea (OSA) will
undergo major surgery every year worldwide. OSA is independently associated
with an increased risk of airway, respiratory and renal adverse outcomes in the
early postoperative period1. Additionally, OSA has been implicated in severe
unanticipated adverse respiratory events and sudden unanticipated death during
postoperative opioid analgesic therapy4. Preoperative diagnosis and treatment
for OSA with continuous positive airway pressure (CPAP) therapy or weight-loss
surgery remains unusual. More than 80% of men and 90% of women who have OSA are
undiagnosed and CPAP therapy adherence is a significant challenge. Preoperative
risk-modification with CPAP therapy or bariatric surgery is poorly studied,
providing a unique opportunity to rigorously evaluate it as a potentially
modifiable intervention to substantially reduce the risk of adverse outcome.
Study investigators have previously shown that opioids are associated with
reduction in genioglossus tone and increased airway instability. In recent
years, our co-research group in Ann Arbor has shown that increased sensitivity
to opioids and not increased opioid dose may be implicated in the occurrence of
sudden unanticipated death4. Despite these concerns, little is known of the
respiratory sensitivity to opioids in patients with OSA. Additionally, Sleep
deprivation and fragmentation are associated with increased risk of acute or
chronic pain states2. Patients with untreated OSA have increased pain
sensitivity2. Thus untreated OSA may contribute to increased postoperative
opioid analgesic requirements, which in turn, may increase perioperative
respiratory morbidity in a dose-dependent fashion. Additionally, it appears
that CPAP therapy may reduce this altered pain sensitivity. However, the
duration of and predictability of treatment effect in different populations has
not specifically been tested. Further, it is unknown if OSA treatment by weight
loss is associated with similar alterations in pain sensitivity or respiratory
sensitivity to opioids. Our contribution from the studies proposed in this
application will be to identify the relationship between altered pain
sensitivity and respiratory sensitivity to opioids in patients with OSA and
determine the effect of treatment of OSA on these outcomes. This contribution
is significant, because it has the potential to fundamentally change current
preoperative management decisions in OSA and significantly alter postoperative
outcomes in these high-risk patients.

Primary Objective
To determine the influence of treatment for OSA opioid-induced respiratory
depression (minute ventilation (Vi); tidal volume (Vt); respiratory rate (RR);
end-tidal pCO2; SpO2).

Secondary Objectives
Aim 2: To determine the influence of treatment of OSA on experimental pain
thresholds and endogenous pain modulation.

This is a prospective longitudinal study on the effect of obstructive sleep
apnea treatment with CPAP therapy alone and CPAP therapy combined with
bariatric surgery on hypoxic ventilatory response and pain sensitivity.
Patients aged 18 yr or older, who are ASA I-IV, and are selected to undergo
bariatric surgery are asked to complete the STOP-BANG questionnaire and the
Brief Pain Inventory (BPI). The STOP-Bang questionnaire is a scoring model
consisting of eight easily administered questions starting with the acronym
STOP-Bang and is scored based on Yes/ No answers (score: 1/0). Thus, the scores
range from a value of 0 to 8. A score of >=5 has shown a high sensitivity and
specificity (88%) for OSA6. The BPI is used to assess the severity of pain and
the impact of pain on daily functions. There is no scoring algorithm, but we
will use "worst pain" as measure of pain severity. The worst pain is scored
with numbers from 0 to 10, with 0 meaning *no pain* and 10 *worst pain. We
will exclude patient with a score for worst pain of 5 and higher. Thereafter, a
PSG will be performed in all patients, which is *standard care*. Patients with
a STOP-Bang score of >=5, BPI *worst pain* < 5 and PSG with AHI<5 of >=15 are
approached for consent for the study. According to the results of the PSG we
will place the patients into two groups (AHI<5 and >=15). The patients with an
apnea-hypopnea index (AHI) >= 15 are diagnosed with moderate or severe OSA.
These patients are placed in group 2 . All these patient will have CPAP
therapy. The Respiratory and Pain studies will be done before the start of CPAP
treatment, 8 weeks after initiating the CPAP treatment and 9 months after the
bariatric surgery. The CPAP treatment will not be stopped. With the studies
after bariatric surgery we will look for an additional effect of the bariatric
surgery and weight loss achieved with the surgery at top of the effect of the
CPAP therapy. Also a PSG will be done 8 weeks after CPAP treatment and 9 months
after bariatric surgery. 9 months after bariatric surgery there will be
significant weight loss to expect an effect on OSA. The PSG 9 months after
bariatric surgery will be done without CPAP. The patients who do not have OSA
(confirmed with the PSG to have an AHI < 5 events per hour) will be the control
group. In this group the Respiratory and Pain studies will be done before the
bariatric surgery and 9 months after surgery. The patients who have OSA but not
moderate or severe i.e. AHI >= 5 and < 15 will not participate in our study in
order to achieve maximum contrast. The treatment of their OSA will follow the
national guidelines. We will include 20 patients in both groups. It is know
that in CPAP treatment the adherence can be an issue. Therefore we will include
patients in the CPAP group until we have 20 patients who succesfully managed
the 8 weeks of CPAP treatment. For excluding obesity hypoventilation syndrome,
before the respiratory studies an arterial blood gas sample will be drawn
(standard care). Anesthesia during the bariatric surgery will not be altered or
standardised. The patients will receive routine analgesic therapy
postoperatively.

Intervention: patients accepted for bariatric surgery meeting all inclusion
criteria and none of the exclusion criteria will be enrolled in the study,
after informed consent is obtained. First, the patients will perform a
STOP-BANG questionnaire (figure 1: study flow chart). Patients with a STOP-BANG
score > 5 will be subjected to a PG (polygraphy). Both the questionnaire and PG
is *standard care*. 20 patients without OSA (STOP-BANG>5; normal PG; AHI<5)
will be enrolled in group 1 (control group). 20 patients with OSA (STOP BANG
>5; PG proven moderate-severe OSA; AHI>15) will be enrolled in group 2. All
study patients will be subjected to a pain threshold study and respiratory
study (paragraph 3.2). Thereafter, bariatric surgery will be performed in group
1 patients. Group 2 will receive 8 weeks of preoperative CPAP therapy followed
by a 2nd respiratory and pain threshold study. 9 months after bariatric
surgery, all study patients will undergo another respiratory and pain threshold
study. Polygraphy before- and 8 weeks after initiation of CPAP is standard
care. However, polygraphy 9 months after surgery is considered additional
intervention.

Study subjects will undertake a 30-minute respiratory study 2 or 3 times at
visits at the pulmonary outpatient clinic. Participation in this study has
minimal risks for the patient. The effects of a small bolus of remifentanil is
highly predictable and is thought to be mild. Remifentanil will be administered
in a setting fully equipped for the monitoring and support of respiratory and
cardiovascular function, and by persons specifically trained in the use of
anaesthetic drugs and the recognition and management of the expected adverse
effects of potent oplolds, includlng resplratory and cardiac resuscitation.
Furthermore, quantitative sensory testing will be performed, including
evaluation of endogenous analgesia pathways (conditioned pain modulation) using
a cold pressor test (CPT). Risks during participation in this study are
negligible. ECG electrodes attached to the skin during the use of the
Nocitrack® device might give some local skin redness or irritability, however
based on former clinical use this is expected to be minimal. Before the
respiratory study starts, an arterial blood sample will be drawn to exclude for
the obesity hypoventilation syndrome. Benefit exists in expanding our knowledge
about the of OSA treatment on opiod induced respiratory depression and offers
potential to fundamentally change current preoperative management decisions in
OSA and significantly alter postoperative outcomes in these high-risk patients.