Academiejaar 2013 – 2014

Postoperative sleep disturbances: a review and an observational study

Mies CRIVITS

Promotor: Prof. dr. Jan Mulier

Co-promotor: Prof. dr. Luc De Baerdemaeker

Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie & Reanimatie

Academiejaar 2013 – 2014

Postoperative sleep disturbances: a review and an observational study

Mies CRIVITS

Promotor: Prof. dr. Jan Mulier

Co-promotor: Prof. dr. Luc De Baerdemaeker

Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie & Reanimatie

De auteur en de promotor geven de toelating deze masterproef voor consultatie beschikbaar te stellen

en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van

het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden

bij het aanhalen van resultaten uit deze masterproef.

Datum: 11/7/2014

(handtekening ASO) (handtekening promotor)

Mies Crivits Prof. dr. Jan Mulier

Inhoudstafel – Table of contents

1. Abstract English ……………………………………………………………………………..…….. 1

2. Abstract Nederlands ……………………………………………………………………………..…….. 2

3. Introduction ……………………………………………………………………………..…….. 3

4. Methodology ……………………………………………………………………………..…….. 5

5. Results literature review ……………………………………………..………………………… 6

Normal sleep architecture .............................................................. 6

Assessment of sleep ……………………………………………..………………………… 7

i. Subjectively ……………………………………………..………………………… 8

ii. Objectively ……………………………………………..………………………… 8

Physiology of sleep ……………………………………………..………………………… 8

Pathophysiology of sleep .............................................................. 10

Postoperative sleep ……………………………………………..………………………… 11

i. Effect of pain on sleep .............................................................. 12

ii. Effect of opioids on sleep ………………………………………………. 12

iii. Effect of non-opioid Anaesthesia on sleep ……………………… 13

- Dexmedetomidine ………………………………………………. 13

- Inhalation anaesthetics ………………………………….. 14

- Local anaesthetics ………………………………………………. 14

- Paracetamol and non-steroidal anti-inflammatory drugs 15

iv. Effect of surgery on sleep ………………………………………………. 15

v. Miscellaneous .............................................................. 16

6. Results observational study ……………………………………………..………………………… 16

7. Discussion ……………………………………………………………………………..…….. 18

8. Conclusion ……………………………………………………………………………..…….. 20

9. References ……………………………………………………………………………..…….. 21

10. Appendix A

English abstract

Introduction: Different studies have shown that sleep disturbances in the first postoperative

nights are common. We will first review the relevance of these sleep disturbances and explore

the possible contributing factors in detail. Next, the observational study we conducted

comparing opioid anaesthesia (OA) versus opioid free anaesthesia (OFA) on sleep quality is

discussed.

Methodology: First, we conducted a thorough literature study using Pubmed, ISI web of

science, Google Scholar and the Cochrane Library. Articles were selected according to their

relevance, using different combinations of following MESH terms: postoperative, opioids,

opioid free anaesthesia, sleep architecture, sleep disturbance and sleep physiology.

Next we conducted a single centre retrospective observational study comparing opioid free

anaesthesia to opioid anaesthesia in adult patients after standard or revision gastric bypass

surgery on their wellbeing and subjective quality of sleep. After the first postoperative night,

sleep quality was assessed using the validated quality of recovery score (QoR-40). This

questionnaire covers different postoperative aspects - the five relevant to the sleep quality

were analysed. The results were statistically processed using the Pearson's chi-squared test.

Results: The aetiology of a disturbed sleep architecture is multifactorial. We explored the

relative contribution of different perioperative factors such as the impact of anaesthesia,

surgical stress, postoperative pain and especially of opioids on sleep architecture. The

observational study included a total of 292 patients. The patients treated in the OFA group

experienced less bad dreams (p = 0.017), felt more comfortable (p = 0.001), reported better

sleep (p = 0.011) and felt better rested (p = 0.012) than patients in the OA group. On the other

hand, we found no impact of the extend of surgery (primary or revision) on the five different

aspects of sleep measured by the QoR-40 scale.

Conclusion: It is well established that the postoperative sleep pattern is severely disturbed.

We conclude that this cannot be solely explained by opioid use alone, which favours the

assumption that the biggest impact on sleep is seen as a result of surgical trauma and

environmental factors. Opioid free anesthesia did result in increased patient sleep quality.

Nederlandstalig abstract

Inleiding: Verschillende studies hebben aangetoond dat patiënten de eerste postoperatieve

nachten ernstige slaapstoornissen ervaren. In deze scriptie wordt de relevantie van deze

slaapstoornissen besproken alsook de mogelijke oorzaken. Verder bespreken we onze

observationele studie waarin de impact op slaapkwaliteit wordt vergeleken na opioïde en

opioïdvrije anesthesie.

Methodologie: Eerst werd een grondige literatuurstudie verricht met behulp van Pubmed, ISI

Web of Science, Google Scholar en de Cochrane Library. Artikelen werden geselecteerd op

basis van hun relevantie, met behulp van verschillende combinaties van volgende MESH

termen: postoperatief, opioïden, opioïdvrije anesthesie, slaaparchitectuur, slaapverstoring en

slaapfysiologie. Vervolgens voerden we een retrospectieve observationele studie uit waarbij

patiënten bevraagd werden naar hun algemeen welzijn en subjectieve slaapkwaliteit. We

gingen hierbij na of er een impact is van opioïde of opoïdvrije anesthesie. Daarenboven

bekeken we de potentiële impact van de uitgebreidheid van heelkunde, waarbij we de

patiënten na standaard of na een revisie gastric bypass met elkaar vergelijken. Na de eerste

postoperatieve nacht werd de slaapkwaliteit gemeten met de gevalideerde ‘Quality of

recovery score’ (QOR-40). Deze vragenlijst heeft betrekking op verschillende postoperatieve

aspecten - vijf relevant voor de kwaliteit van slaap werden geanalyseerd. De resultaten

werden statistisch verwerkt met behulp van de Pearson chi-kwadraat test.

Resultaten: De etiologie van een verstoorde slaaparchitectuur is multifactorieel. We

verkenden de relatieve bijdrage van de verschillende perioperatieve factoren zoals de effecten

van anesthesie, chirurgische stress, postoperatieve pijn en vooral opioïden op de

slaaparchitectuur. De observationele studie omvatte 292 patiënten. De patiënten in de

opioidvrije groep ondervonden minder slechte dromen (p = 0,017), meer comfort (p = 0,001),

betere nachtrust (p = 0,011) en voelden zich beter uitgerust (p = 0,012) dan patiënten in de

opioïde groep. Daarentegen vonden we geen invloed van de uitgebreidheid van chirurgie

(primair of revisie) op de vijf verschillende aspecten van de slaap gemeten door de QOR-40

schaal

Conclusie: Het is bekend dat het postoperatieve slaappatroon ernstig verstoord is. We

concluderen dat dit niet alleen door het gebruik van opioïden kan verklaard worden. Dit

ondersteunt de veronderstelling dat het grootste effect op slaap een gevolg is van chirurgisch

trauma en omgevingsfactoren. Opioïd vrije anesthesie resulteerde wel in een verbeterde

slaapkwaliteit.

Introduction

Although the perioperative risks related to anaesthesia and surgery have greatly diminished

over the years, surgery is still beset with postoperative complications. The in-hospital

mortality and morbidity the first two postoperative months is still high as recently measured

by Pearse.1 Different types of complications including pulmonary, cardiac, thrombo-embolic

and cerebral dysfunctions, are likely not solely explained by inadequate surgical or

anaesthetic techniques.

The major disturbances seen after surgery are not merely discomfort. One of the observations

is that sleep quality is frequently disturbed the first postoperative days. The changes in sleep

architecture include sleep fragmentation, reduced total sleep time and loss of time spend in

slow wave sleep (SWS) and rapid eye movement (REM) sleep.2

We will first discuss the relevance of sleep disturbances. After which we will explore in more

detail the possible contributing factors. We also include an observational study comparing

opioid anaesthesia versus opioid free anaesthesia on sleep quality.

Disturbed and rebound REM sleep

Rapid eye movement (REM) sleep is a short moment of high autonomic nervous system

activity, which could be stressful for the body, especially after surgery. This REM sleep

accounts for 25% of total sleep time during a normal night. Interestingly, if suppressed for one

or more nights, rebound REM sleep occurs the following nights, which resembles REM sleep

but with an increased intensity and duration.

Various studies have been able to show that REM sleep is diminished or even completely

abolished in the first postoperative nights and thus is followed by rebound REM sleep the

consecutive nights.3 During REM sleep and its coupled episodes of apnea, ventricular

tachycardia and severe bradycardia are common and this may impose additional stress on

underlying heart disease, especially after major surgery where important fluid and electrolyte

shifts have taken place. This is even more so as the effects of REM are intensified during

rebound REM sleep.3

As reported by Kaw3, rebound REM sleep is associated with a threefold increase in hypoxic

episodes. This may account for the observation made by Hung et al.4 where in a group of

unselected male survivors of acute myocardial infarction, an apnoea index of more than 5,3 is

an independent predictive factor for the development of a myocardial infarction. This

hypothesis is further supported by the fact that the majority of unexplained postoperative

deaths occur at night in the first postoperative week. The highest incidence of postoperative

cardiac complications occurs during the first three postoperative days, with a peak on the third

day. This coincides with the time window where there is a state of rebound REM sleep.5

Rebound REM sleep has also been linked with obstructive sleep apnoea syndrome, stroke,

myocardial infarction, mental confusion, delirium, and haemodynamic instability and wound

breakdown.3

Disturbed sleep and pain

Despite the presence of effective analgesics, acute postoperative pain control is insufficient in

about 30% of the patients. Importantly, of those patients 2-10% develop severe chronic pain.2

Sleep and pain interact bidirectional: sleep deprivation has a hyperalgesic effect and pain

disturbs the sleep architecture.6 In the postoperative setting there are additional factors that

may disturb sleep architecture, including suboptimal sleep environment, medication

interaction and the biochemical response to the surgical insult.

To exclude these confounding factors, Roerhs et al.7 conducted a study in healthy, pain free

volunteers. As a measure of the subjects pain threshold, the finger withdrawal latency to a

thermal stimulus was recorded after normal and reduced total sleep time. A reduction from

eight to four hours of sleep resulted in a reduction of the finger withdrawal latency with 25%.

Secondly they confirmed that a loss of REM sleep also decreased the pain threshold with a

32% loss of latency. Roerhs showed a clear effect on the pain threshold of reduced total sleep

time and reduced REM sleep. However according to Lauterbacher it remains unclear whether

it is the sleep continuity disturbance per se or the loss of sleep-specific stages that is

responsible for the decreased pain threshold.6 Neither are all types of noxious stimuli in the

same way affected. It seems that pressure pain tolerance is more easily affected than heat pain

tolerance.8

There are multiple causal factors that may partially explain this phenomenon:7

- REM sleep deprivation decreases cholinergic activity, and acetylcholine (ACh) is known to

promote both analgesia and REM sleep

- REM sleep deprivation depletes brain stem levels of serotonin and some data show that

serotonerg cells are active in the brainstem inhibition of nociception

- a stimulation of excitatory amino acids like glutamate which have a influence through

descending pain control pathways

- an impact on the endogenous opioid system with a reduced binding to mu and delta

receptors

- an inflammatory process is also proposed. Haack showed increased amount of interleukin-6

(IL-6) after prolonged sleep deprivation.9 IL-6 is associated with pain related discomfort.

6

- there is also a psychological factor that can influence pain perception as sleep deprivation

has an impact on attention, anxiety and the emotional state.6

Methodology

This paper is divided into two parts, a literature and an observational study.

Articles for the literature study were gathered using Pubmed, ISI web of science, Google

Scholar and the Cochrane Library. Articles were selected according to their relevance, using

different combinations of following MESH terms: postoperative, opioids, opioid free

anaesthesia, anaesthesia, surgery, sleep stages, sleep architecture, sleep disturbance and sleep

physiology. Inclusion criteria for the literature search were limited to the English language.

Human and animal studies were included. Editorials, case reports, and duplicates were

excluded. Narrative reviews were reviewed to confirm an exhaustive review of the scientific

literature. All references were evaluated from the manuscripts to confirm inclusion of all

pertinent studies. Two investigators independently screened the identified article titles and

abstracts, and independently assessed the risk of bias.

Next we conducted a single centre retrospective observational study comparing opioid free

anaesthesia to opioid anaesthesia in adult patients. In this study we questioned all patients

over a period of two months who had a standard or revision gastric bypass surgery on their

wellbeing and subjective quality of sleep on the first postoperative day. Patients received

opioid free anaesthesia (OFA group) by half of the anaesthesiologists while the other

anaesthesiologists gave traditional opioid anaesthesia (OA group) with sufentanil. Patients

who got an opioid sparing method, consisting of a combination of maximum 10 µg sufentanil

with dexmedetomidine were excluded. Urgent surgery was also excluded. In the opioid

group, the dose of sufentanil was between 15 and 50 µg according to the anaesthesiologists

discretion. The opioid free group received dexmedetomidine at maximum 1 µg.kg-1.h-1,

lidocaine at maximum 1,5 mg.kg-1.h-1, magnesium at 5 mg.kg-1.h-1, a low dose ketamine of 25

mg and inhalation anaesthesia below 1 MAC. Postoperative pain was treated using a

predetermined flowchart, until VAS < 3. Non opioid drugs (paracetamol and diclofenac) were

used first and opioids (piritramide and morphine) were added if pain treatment was

insufficient. After the first postoperative night, sleep quality was assessed using the validated

quality of recovery score (QoR-40 score – see appendix A).10

This questionnaire covers

different postoperative aspects, but only the five relevant to the sleep quality were analysed.

Following topics were covered: having a good sleep, difficulty in falling asleep, bad dreams,

feeling rested and feeling comfortable. Three other questions have been added to control the

impact of moderate pain, nausea and feeling too cold on the effect of sleep quality. The results

were statistically processed using the Pearson's chi-squared test.

Literature

Normal sleep architecture

There are two standards for the analysis of sleep, one published in 1968 by Rechtschaffen and

Kales, the other in 2007 by the American Academy of Sleep Medicine. In the literature both

standards are still used. In this paper we will describe the stages and architecture of sleep

according to the most recent standard.

Sleep is analysed in 30 second phases which can be divided into rapid eye movement (REM)

sleep and non-rapid eye movement (NREM) sleep based on their electrophysiological

patterns.

Figure 1 - Normal adult hypnogram demonstrating usual sleep stage transitions. REM

indicates rapid eye movement sleep, N1 through N3 are the three different NREM sleep

stages according to the American Academy of Sleep Medicine. (Kamdar et al.11

)

REM sleep covers 20 to 25 percent of the total sleep time and is characterized by three main

features:

- a low voltage, fast frequency electroencephalogram (EEG) pattern that resembles an

active, awake EEG pattern

- rapid eye movements

- an atonic electromyogram (EMG) indicating inactivity of all voluntary muscles,

except the extraocular muscles. The atonia is the result of direct inhibition of the

alpha motor neurons.

REM sleep is further divided into phasic REM sleep and tonic REM sleep. During phasic

REM sleep there are bursts of rapid eye movements associated with brief burst of muscle

activity, seen on EMG. Tonic REM sleep is the sleep between the phasic bursts. Although

REM sleep is typically a parasympathetic state, there is sympathetic activity during phasic

REM sleep. The sudden increase in sympathetic activity gives rise to an increase in arterial

blood pressure, heart rate and/or respiratory rate with an increased risk of cardiac ischemia,

cerebral ischemia and cardiac arrhythmias. Short central apnoea’s, hypopnoeas and long

cardiac systoles have also been reported.12

NREM sleep is subdivided into different stages. The original standard of Rechtschaffen and

Kales recognized four stages (N1 to N4), however the newer standards fused stages N3 and

N4 so that only three stages of NREM sleep are described.

Stage N1 is the transition from wakefulness to sleep and is the lightest sleep stage. It is

characterised by low amplitude, relative fast EEG frequencies in the theta range (4 to 7 Hz)

and accounts for 2 to 5 percent of the total sleep time. Stage N2 sleep is called intermediate

sleep and shows on EEG a slowing of the frequency and an increase of the amplitude. This

stage accounts for 40 to 50 percent of the total sleep time. Stage N3 is referred to as the deep

sleep or slow wave sleep (SWS), is characterised by low frequency, high amplitude delta EEG

waves and accounts for 20 percent of the total sleep time.

The sleep stages occur in 90 to 120 minute cycles, with four to five cycles in a normal night.

The first cycle starts with a briefly passing from wakefulness to N1 sleep and then to stages

N2 and N3. Subsequent cycles consist of N2, N3 and REM sleep. During the second half of

the night N2 and REM sleep alternate. N1 and N3 are usually absent.

Assessment of sleep

To study and compare the quality of sleep, validated systems are indispensable. Sleep can be

measured subjectively and objectively. Although validation between both is sometimes

assumed13

, this assumption has not been definitively proven.

Subjectively

According to Rosenberg it is possible to evaluate the subjective sleep quality simply by

asking the patient how he perceived his sleep. It shows to be related to total sleep duration and

the number of awakenings.14

However more accurate questionnaires have also been designed to obtain information about

different aspects of sleep.8 The Stanford sleepiness scale is an eight-item questionnaire used

to assess sleep deprivation. The Epworth sleepiness scale is also an eight-item questionnaire

measuring subjective daytime sleepiness. It has been evaluated in sleep apnoea. The Leeds

sleep evaluation questionnaire uses ten 100mm line analogue scales to measure the perceived

changes to sleep caused by medication. The Pittsburgh sleep quality index probes about the

sleep habits during the previous month, and also includes information from the sleeping

partner. The St Mary’s sleep questionnaire is designed for hospitalized patients to evaluate the

state of sleep and wakefulness during the preceding 24 hours.

Objectively

Objective measurement is a must to study sleep disturbances since they may reveal and

quantify more subtleties than a questionnaire. Also, it has been shown that subjective

observation by a third person, such as the nursing staff, strongly overestimates the actual

sleeping time of the patients.15

The laboratory polysomnography (PSG) is considered to be the golden standard. PSG

continuously and simultaneously records physiological variables during sleep. For an analysis

of sleep states and sleep architecture the PSG must record, as a minimum, the

electroencephalogram, the electro-oculogram and the chin electromyogram. Routinely the

electrocardiogram and respiratory variables such as nasobuccal airflow, thoracoabdominal

respiratory movements, pulse-oxymetry and snoring are also recorded.

Actigraphy is a more flexible technique that monitors periods of rest and activity. Sleep is

detected by asking the patient to maintain a sleep journal. This tool is used to study disorders

in sleep-wake rhythm as well as tremor, periodic leg movement and insomnia but cannot be

used in bedridden patients.

Physiology of sleep

Two processes that keep each other balanced regulate the sleep-wake cycle. The process S

defines the drive to sleep and is primarily regulated by adenosine, the end product of the

adenosine triphosphate metabolism, and by melatonin, secreted by the pineal gland.

The opposite, the wakefulness, is regulated by the process C, which is the circadian

pacemaker, situated in the suprachiasmatic nucleus. Neural pathways that inhibit melatonin

secretion when exposed to light and a mixture of different neurotransmitters including orexin,

acetylcholine, serotonin, norepinephrine, dopamine and histamine modulate this process.11

During sleep the body experiences a lot of physiological changes, important for growth and

homeostasis:11

- respiratory physiology

Voluntary control is lost during sleep with a decreased response to hypoxia and hypercarbia.

During REM sleep respiration is very variable with changes in minute ventilation, respiratory

rate and tidal volumes. This variability is most pronounced during bursts of phasic REM.

- cardiovascular physiology

During NREM sleep there is autonomic stability with a parasympathetic overtone. On the

contrary, during REM sleep there is a marked variability. Tonic REM sleep is characterized

by vagal bursts leading to brady arrhythmias and sinus pauses. Phasic REM is dominated by

increased autonomic activity with transient increases of 35% in heart rate and blood pressure.

- gastrointestinal physiology

Throughout sleep oesophageal motility decreases while gastrointestinal motility remains

constant. Gastric acid secretion follows a circadian rhythm with a peak in early sleep.

- thermoregulation

Temperature sensitivity decreases during NREM and is completely abolished during REM

sleep. Body temperature is at its lowest during the end of sleep, followed by a rise in

temperature preceding awakening.

- endocrine physiology

Some anabolic hormones, like growth hormone and prolactin follow a sleep-wake cycle and

the secretion is suppressed when sleep is restricted. Other hormones, like cortisol and thyroid

stimulating hormone, have a circadian pattern. Secretion of thyroid stimulating hormone is

inhibited by SWS sleep and rises when sleep deprived.11

There is no agreement on the exact function of sleep. Several theories exist, none of which

have been proven to this point. The most widely accepted is the restorative sleep theory,

which states that the process of sleep restores tissues and prepares the body and brain for the

next day.14

Total or selective sleep deprivation affects particularly the brain, with

psychological and neurological dysfunction as an impaired behavioural and psychological

performance, sleepiness and an impaired concentration and performance on psychometric

tests. Mood is also affected with increased sadness and irritability. The adaptive theory of

sleep is an evolutionary theory and proposes that sleep increases survival as it immobilises the

body during the most dangerous time of the day. Finally the energy conservation theory states

that the function of sleep is to provide an interval during which there is a reduced metabolism

and the possibility to conserve energy.

Likewise the purposes of REM and NREM sleep remain uncertain. REM sleep appears to be

an essential part of sleep since animals with REM sleep deprivation die after several weeks.16

Furthermore the need to compensate for lost REM sleep with rebound REM sleep also

suggests that insufficient REM sleep is detrimental.17

It has been proposed that REM sleep has

an important role in memory consolidation.18

During SWS there is a homeostatic process for

mind and body in which there seems to be a release of anabolic hormones and an increase in

immune activity.8

Pathophysiology of sleep

In sleep deprived patients, different physiologic changes have been described:11

- respiratory changes

In healthy volunteers 24 to 30 hours of sleep deprivations leads to respiratory muscle

weakness and a decreased ventilatory response to hypercapnia.

- cardiovascular changes

Sleep deprivation leads to an increased sympathetic and decreased parasympathetic tone and a

state of increased catecholamine release resulting in high blood pressure and heart rate and as

such an increased risk of acute myocardial infarction. Furthermore endothelial disruptions are

caused by the release of inflammatory cytokines.

- immunologic changes

In animal settings the necessity of sleep for an adequate immune response has been shown.

Prolonged sleep deprivation onsets a catabolic state with opportunistic infections followed by

septicaemia and death in 27 days. In humans the relationship between sleep deprivation and

immunology is less clear. Data suggest that it affects cellular immunity and cytokine function

but the exact mechanism and clinical implications are not known.

- hormonal and metabolic changes

There is a rise in cortisol levels and catecholamine release, reflected by the increased

metabolic indices as oxygen consumption and carbon dioxide production. The same

circumstances are present in patients with sepsis, which may suggest that sleep deprivation

intensifies the stress response. Also glucose metabolism is changed with a decreased

sensitivity to insulin and impaired glucose tolerance.

- psychological changes

Delirium is the best know psychologic postoperative complication. It can also be present in

critically ill patients. Although the exact contribution of sleep deprivation to the development

of delirium is not clear, both conditions share important mechanisms, risk factors and

symptoms.11

Postoperative sleep

Multiple observations show intense postoperative sleep disturbances with a complete

abolishment of REM sleep the first postoperative night, a reduced amount of SWS, an

increase in light NREM sleep, a reduced total sleep time and an increased amount of

awakenings.8 Typically the REM sleep reduction is compensated in the next postoperative

nights by a rebound REM sleep occurring on the second and third postoperative night.

In 1985 Aurell and Elmqvist15

studied 9 patients after non-cardiac surgery. All were sleep

deprived afterwards. The cumulative sleep time over the first 48 hours postoperative was less

than 2 hours a day. REM sleep and SWS were completely suppressed. Several factors may

contribute to this disturbed sleep pattern postoperatively.

Figure 2 - Schematic diagram of the relationship between sleep disruptions, opioid use,

and postoperative pain, and respective contributing factors. Filled arrows represent the

relationship and clear arrows represent contributing factors. (Chouchou et al.2)

Effect of pain on sleep

As mentioned earlier, sleep deprivation can lead to an increased pain perception the next day.2

Reciprocally, pain itself can alter sleep and sleep architecture. It is often assumed that

effective pain relief is enough to restore sleep architecture. However, most medications used

to treat pain, also affect the sleep process.

Effect of opioids on sleep

Opioids have been suggested as a causal factor in the postoperative sleep disturbances. We

have to consider the intrinsic bias, considering the inverse relationship between opioids and

pain. To rule out the factor of postoperative pain, we will first review the studies on healthy,

pain free subjects.

In 1969 Kay et al.19

concluded that morphine increases the wakefulness and inhibits the REM

sleep and SWS in a dose dependent manner. Administration of 0.22mg/kg morphine reduced

REM by 50%; 0.43mg/kg abolished REM sleep completely. In 1987 Moote also confirmed a

REM sleep and SWS suppression with doses of morphine ≥ 0,2mg/kg.20

It has to be noted that a lot of the earlier studies were conducted on opioid addicted patients.

In experiments on catsthey also measured a dose dependent inhibition of REM sleep by

opioids, which was reversible by naloxone and hence receptor subtype specific.21,22

Cronin et

al. injected synthetic opioid agonists selective for mu, delta and kappa subtypes of opioid

receptors into the medial pontine reticular formation (mPRF) in awake cats and studied the

polysomnographic recordings. The results support the hypothesis that inhibition of REM sleep

is at least partially caused by a direct effect on mu receptors in the mPRF22

. More studies23,24

have demonstrated a cholinergic control of REM sleep. Injection of atropine into the mPRF

inhibits natural REM sleep.22

Opioids have the ability to inhibit the release of acetylcholine

and this pathway accounts for an indirect negative effect on REM sleep.

Cronin et al.25

tested the hypothesis that opioids disturb postoperative sleep independently of

pain by conducting a study in 2001 on nine people undergoing a gynaecological procedure

requiring a low abdominal incision. Five of them received postoperative pain control by

patient controlled epidural anaesthesia (PCEA) with solely opioids (fentanyl), the other four

patients received a PCEA with local anaesthetics (bupivacaine). Polysomnographic control

was performed on the preoperative night and the first three postoperative nights. In both

groups there was a complete abolishment of the REM sleep on the first postoperative night,

compensated by an increase in light NREM sleep. In the second night there was already an

increase in REM sleep. The only significant difference between both groups was the SWS. On

the second postoperative night SWS was lower in the group on opioids, compared to the

group on local anaesthetics.

In 2005 Shaw conducted a study on opioid naive patients.13

Seven patients underwent a PSG

in a crossover design with 3 different data points: at baseline, after administration saline and

after morphine 0,1mg/kg. They concluded an overall shift to lighter sleep with a 75%

reduction in SWS, 5% reduction in REM sleep and an increase of 15% in NREM sleep. The

total sleep time did not alter. There was a reduction of total sleep time between baseline and

morphine but there was no difference between morphine and placebo suggesting that injection

on its own caused more stress and therefore less total sleep time. Although they saw

significantly more arousals in the morphine group, they were still in the physiologic range.

Furthermore, subjectively the patients didn't notice a difference in sleep quality between the

three different settings and the changes in sleep architecture measured in the study are less

pronounced than the typical changes seen postoperatively. Bonafide argues that, since

previous studies always applied opioids before the start of the data recording, it is possible

that the increased awakenings are caused by the agitation of opioid withdrawal.28

To reduce

this bias Bonafide et al. used a continuous infusion of remifentanil. They noted a significant

reduction in REM sleep with a 72% decrease even at low concentration of remifentanil (0,01-

0,04ug.kg-1

.h-1

). There was a decrease in SWS of 53% and an increase of wake time of 58%

but this was not significant.

Another plausible explanation for the reduction in REM sleep and SWS after opioids could be

that they derange the circadian pacemaker. To test this hypothesis they measured the

melatonin concentration at different times during the night, which remained normal. Then

they administered exogenous melatonin in the assumption that it would restore REM sleep

and SWS, but it did not. Furthermore although remifentanil decreases REM sleep, the REM

sleep distribution, with a predominance in the second half of the night, remains. Therefore

they could confirm that opioids do change sleep architecture and that it is not because of

withdrawal nor because of a disturbance of the circadian pacemaker.

Effect of non-opioid anaesthesia on sleep

- Dexmedetomidine:

Functional MRI shows a change in local brain activity in patients sedated with

dexmedetomidine similar to the activity seen in natural occurring sleep. Binding of

dexmedetomidine to the α2-a adrenoreceptor in the pontine locus ceruleus hyperpolarizes the

noradrenergic fibres decreasing their firing rate.22

Nelson et al. postulate that the loss of

consciousness seen with dexmedetomidine is via the activation of an endogenous sleep

promoting pathway through an inhibition of the release of norepinephrine in the locus

ceruleus. This mimics NREM sleep and enhances SWS, but at the same time it inhibits REM

sleep since norepinephrine has a REM sleep permissive role.27

Oto et al. tested the hypothesis

that dexmedetomidine favours NREM sleep.28

They did this in a population of mechanically

ventilated patients on intensive care unit (ICU). Although this isn't quite the typical

postoperative setting, it has been shown that there are similar sleep architectural changes on

the ICU with a loss of REM sleep and SWS.29

Additionally they see a scattered sleep pattern

where half of the sleep is during the day and the other half during the night.30

In this study

they administered a continuous infusion of dexmedetomidine only during the night. All types

of sedation were interrupted during the day, within comfort limits of the patient. Twenty-four

hour PSG recordings were taken in 10 patients.28

They found a remarkable shift of sleep to the

night-time versus daytime and the arousal index was within normal limits. However the sleep

measured during the night existed mostly of NREM stage 2 sleep with an almost complete

absence of REM sleep and SWS. There may be a lot of confounding factors in this study and

even though they saw a clear improvement of the circadian pattern, it is plausible that the

daytime interruption of sedation is at least partially responsible for this result since it has been

shown that continuous sedation reduces melatonin secretion.31

- Inhalation anaesthetics

In 1988 Moote saw a reduced amount of SWS after the use of isoflurane, without an effect on

REM sleep.32

Nonsurgical volunteers were kept under anaesthesia using isoflurane for three

hours. They only noticed a modest reduction in SWS for one hour, with no effect on REM

sleep.

In 2007 Steinmetz conducted a prospective study in 39 children comparing postoperative

sleep in two therapeutic and one control group.33

The effects of anaesthesia conducted with

sevoflurane and those conducted with propofol-remifentanil were observed with attention to

subjective sleep quality, measured by a questionnaires completed by the parents. The

hypothesis was that children would have more disturbed sleep after sevoflurane because

emergence agitation is more common after inhalation anaesthesia. However the longest

continuous sleep was significantly longer in the sevoflurane group. In both groups there was

an significantly impaired sleep pattern, returning back to normal after 10 days, with no

difference between groups.

- Local anaesthetics

A recent study by Dette et al. looked at the sleep phases after surgery under regional

anaesthesia.34

There were no opioids administered the first three postoperative days. PSG

recordings were made the night preoperative and the first and fifth postoperative night. The

same sleep disturbances were seen as after general anaesthesia with a decrease in REM sleep,

SWS and total sleep time the first postoperative night and a -almost- normalisation on the fifth

night. It must be stated that this study was performed on 12 patients and couldn’t attain

sufficient power.

- Paracetamol and non-steroidal anti-inflammatory drugs

Smith stated in 1985 that paracetamol has a positive effect on sleep, even in individuals

without pain.35

Murphy could not confirm the positive effect, but could not detect a negative

effect either in his study in 1994.36

It used to be presumed, after a study by Lavie in 199137

, that non-steroidal anti-inflammatory

drugs (NSAID) had a negative impact on sleep architecture with an increase in arousals and

light NREM sleep, and a decrease in SWS and overall sleep efficiency. More recently

however Gengo et al.38

refuted this in their study a PSG was recorded at baseline and after a

total of 1200 mg ibuprofen. They could not detect any effect on sleep architecture.

Effect of surgery on sleep

The fact that similar sleep patterns are observed after regional anaesthesia and in the ICU, as

compared to after general anaesthesia, suggests that sleep changes aren’t merely caused by

general anaesthesia. Critically ill patients show a fragmented, light sleep with lack of SWS

and REM sleep. This observation supports the hypothesis that stress, illness and possibly also

environmental factors play an important role.11

Knill et al. measured the sleep quality after open cholecystectomy (CCE) with gastroplasty

and found the typical strong sleep deviations.39

Rosenberg observed in 1994 similar findings

after extensive abdominal surgery.40

On the contrary, two years later Rosenberg observed the

sleep architecture following laparoscopic CCE was found a postoperative undisturbed REM

sleep and only a slight reduction in SWS with a compensatory rise in light NREM sleep.41

Already in 1976 Ellis stated that the extend of surgery might correlate with the magnitude of

sleep deviations.42

Surgical stress and trauma on its own may be the main factor in the postoperative sleep

disturbance due to a endocrine, autonomic and inflammatory stress response to surgery.2

Tissue trauma and surgical stress cause a release of cytokines like interleukin-1, tumor

necrosis factor alfa and IL-6, known to have a negative effect on REM sleep and SWS.2,25

Another effect of surgery is the rise of cortisol. Cortisol reduces REM sleep, but to a lesser

extend as seen postoperatively. Furthermore cortisol even increases SWS.2,25

Miscellaneous

Many other non medical factors, like circadian rhythm, sleep environment, chronic sleeping

problems, ... can also influence sleep and might be even more important. However this is

beyond the scope of this review.

Observational study

We conducted an observational study comparing sleep quality in patients receiving opioid

anaesthesia (group OA) to patients undergoing opioid free anaesthesia (group OFA). A

second analysis was done to assess the possible impact of the extend of surgery on sleep

quality comparing first time to revision Roux en-Y (RNY). The methodology of this study

was explained earlier in the chapter Methodology (p5).

We included 292 patients in a time period of 2 months. Eight patients were lost in follow-up

because two patients were already dismissed out of the hospital, five patients were not

available on two different occasions and one patient wasn’t able to answer the questions

because she was being scheduled for an urgent revision. There were no significant differences

found between the different groups in number, age, length and weight. (table 1)

tota

l

patients

type of

surgery

patients

age length in cm weight in kg

mean SD mean SD mean SD

group OA 145 first RNY 105 41.72 13.97 168.82 9.38 113.15 14.89

revision RNY 40 41.41 11.94 168.17 9.65 116.79 23.47

group

OFA 147

first RNY 102 40.47 13.44 167.52 9.62 111.04 17.58

revision RNY 45 49.07 12.09 167.63 10.86 116.74 30.56

table 1 – Demographic data on the patients. SD: standard deviation

The QoR40 questionnaire includes five questions relevant to sleep. Table 2 gives the number

of positive answers for the OFA versus OA and table 3 states the number of positive answers

for the first bariatric surgery versus the revision bariatric surgery. Three other questions of the

Qo40 on nausea, feeling cold and experiencing moderate pain were included. This was done

because they could have an effect on sleep quality. Statistical analysis was performed using

the Pearson’s Chi-square test with a α type 1 error of 0.05.

OA OFA P-values

feeling comfortable Y/N 103/42 128/18 0.001

% 71.0 89.5

bad dreams Y/N 8/137 1/145 0.017

% 5.5 0.7

difficulty falling asleep Y/N 59/86 62/83 0.759

% 40.7 42.8

having a good sleep Y/N 41/104 62/84 0.011

% 28.3 42.5

feeling rested Y/N 68/77 90/54 0.012

% 46.9 62.5

nausea Y/N 58/87 39/107 0.016

% 40.0 26.7

feeling too cold Y/N 35/110 13/133 0.001

% 24.2 8.9

moderate pain Y/N 95/50 70/76 0.002

% 65.5 47.9

Table 2 - Result of Chi square analysis Group OA compared to Group OFA.

Statistical significant P-values are represented in bold.

first RNY revision RNY P-value

feeling comfortable Y/N 162/44 69/16 0.627

% 78.6 81.2

bad dreams Y/N 7/199 2/83 0.64

% 3.4 2.3

difficulty falling asleep Y/N 91/114 30/55 0.162

% 44.4 35.3

having a good sleep Y/N 66/140 37/48 0.062

% 32.0 43.5

feeling rested Y/N 117/87 41/44 0.183

% 57.4 48.2

nausea Y/N 63/143 34/51 0.121

% 30.6 40

feeling too cold Y/N 30/176 18/67 0.167

% 14.6 21.2

moderate pain Y/N 120/86 45/40 0.406

% 58.2 52.9

Table 3 - Result of Chi square analysis first RNY compared to revision RNY.

The patients treated in the OFA group experienced less bad dreams(p = 0.017), more feelings

of comfort (p = 0.001), had more reports of good sleep (p = 0.011) and felt better rested (p =

0.012) than patients in the OA group. However we could not detect a difference in ease of

falling asleep between both groups (p = 0.759). On the other hand, we found no impact of the

extend of surgery (primary or revision) on the five different aspects of sleep measured by the

QoR-40 scale. Patients felt that the primary cause of not being able to fall asleep was the fact

that they weren’t home in their own bed, followed by noise and nursing activity during the

night.

Furthermore patients receiving OFA felt less nausea (p = 0.016), less cold (p = 0.001) and less

moderate pain (p = 0.002) compared to those in the OA group. The postoperative necessity

for opioids was also recorded. There was a significant lower use of piritramide (dipidolor®)

in the OFA (6 +/- 9 mg) group than in the OA group (16 +/- 10 mg) with a p-value of 0.001.

So these results suggest that type of anaesthesia and not type of surgery has an impact on the

sleep quality. Nausea, feeling too cold and moderate pain are also related to type of

anaesthesia and not to type of surgery.

Discussion

As we review the literature some inconsistencies become apparent. Shaw13

couldn’t measure

the same profound impact on sleep architecture as Kay19

did. A valid reason could off course

be the limited amount of subjects studied (n=7). Although the opiate doses used by Shaw et

al. were relatively small at 0.1 mg/kg of morphine, it could also imply that non dependent

opioid addicts, the test population in Kay's study, have a different arousal response to

additional opioid administration than opioid naive people do.

Possible mechanisms are found that explain the effects of opioids on sleep. Osman conducted

two sets of experiments on rats to test and confirm the role of Ach.43

They found that opioids

cause a concentration dependent and naloxone-sensitive decrease in ACh release in the

prefrontal cortex. This most anterior part of the cortical region has different major functions

as the regulation of arousal, autonomic control and cognitive processing.

Also the higher incidence of delirium can be explained by this mu receptor specific decrease

in ACh since the cortical ACh is essential for normal cognition and sleep.43

There are some

limitations to this study though. First of all it is a study on rats and the relevance for humans

is not known. Although there is much information about the prefrontal cortex in primates and

similar results has been found in mice so this suggests the results are generalizable, rather

than species specific. The study also doesn’t exclude the possibility that other

neurotransmitters can have an additional role as well.

The study by Cronin et al. compared sleep disturbances in two groups, where the only

difference was the administration of opioids or local anaesthetics.25

This study confirms the

profound sleep disturbances postoperative and found it to be independent of the anaesthetic

technique used. They concluded that this should be viewed as evidence for additional

unidentified and more powerful REM sleep inhibiting influences in postoperative patients.

Concerning the observational study we can comment that there was no randomization and

therefore patients receiving opioid free anaesthesia could have been selected on basis of

obesity, obstructive sleep apnoea syndrome, metabolic syndrome or other comorbidities in

request for special attention. This means that difficult, longer and high risk patients could

have got more OFA than OA. Nevertheless there was no significant difference in age, body

weight or procedure type between OFA and OA groups.

The revision bariatric surgery normally, but not always, takes longer and induces more

surgical and peritoneal trauma. Nevertheless type of surgery had no impact on sleep quality

questions, in contrast to what has been seen in other studies. It can be assumed that the

difference in surgical stress of a open versus laparoscopic CCE is much more pronounced

than the difference of a first versus a revision RNY.

OFA gives less nausea, less cold feeling and less pain postoperative while the total dose of

opioids postoperative is also significant lower. It is possible that this better outcome allows

patients to have a better first night sleep and that the opioids are not directly responsible for a

sleep disorder.

Sleep is however not perfect in the OFA group either. Difficulty falling asleep is even very

bad and not different between both groups. And again, environmental factors were reported

as major reason why patients could not fall asleep

In contrast to Cronin25

, we could detect a difference in postoperative sleep quality depending

on the anaesthetic technique used. An important bias in Cronins study is the fact that they

were only partially successful in separating the influences of opioids and pain since the

bupivacaine group tended to have slightly more pain than the opioid group.

Furthermore, only 5 aspects of sleep were observed with this questionnaire. It is very well

possible that there is a difference on PSG. An important bias is that both groups received

opioids in the postoperative setting. The OFA group got significant less piritramide and had

less moderate or severe pain postoperative. During laparoscopy the pneumoperitoneum with

CO2 causes also peritoneal ischemia and inflammation on areas without any surgical activity.

This peritoneal damage is dependent on surgical time, insufflation pressure and several other

factors. OFA could be also protective here and explain the lower inflammation and reduced

pain.

Sleep improvement after surgery requires therefore a multimodal approach in which reducing

the surgical trauma and peritoneal ischemia is probably the most important aspect.

Anaesthesia can have an impact on it and therefore it is important to study its effects more in

detail.

Conclusion

In the postoperative setting there are many different factors accountable for a disturbed sleep.

For one, pain is a very important cause of disturbed sleep. Although assumed that pain relief

is the most effective way to resolve this problem, thought must be given that pain medication

on its own also disturbs the sleep architecture. The commonly used opioids have an irrefutable

role in the postoperative changes in sleep architecture as proven by multiple independent

studies. Also the question of how these changes are caused is more and more answered.

Additionally, the postoperative sleep pattern is more severely disturbed than can be explained

by opioids alone. And even when opioids are completely avoided postoperatively, sleep

disturbances remain. This favours the assumption that the biggest impact on sleep is seen as a

result of surgical stress, tissue trauma and environmental factors.

Due to the multitude of possible confounders during the postoperative setting it remains

difficult to separate the impact of each of these factors on the sleep.

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Appendix A