Series: Volume 6, Issue 2 2015

There are potential benefits and drawbacks when double gloving in the operating theatre. Working in the operating room is associated with a high risk of contact with bodily fluids. To prevent breaches of surgical gloves in theatre it has been suggested in the literature that using two pairs of gloves (double gloving) could provide benefit.  Double  gloving  reduces  the  amount  of  contact  with the patient’s blood and is also effective at reducing the level of exposure to infectious material during needle stick injury. Double gloving also reduces the risk of perforation compared to single gloving. However, it is suggested that double gloving may actually compromise manual dexterity, tactile sensitivity and 2-point discrimination. In conclusion, double gloving does provide greater protection  against  infection  transmission  than  ‘single  gloving’ in relation to intraoperative glove perforation and needle stick injuries, and does not appear to compromise surgical performance.

Introduction

Working in the operating room is associated with a high risk of contact with bodily fluids, especially for surgeons. [1] Transmission of an infection from a patient to a surgeon or other operating room staff occurs through mucocutaneous or percutaneous transmission, such as a needle stick injury. [2] Transmission of blood borne viruses such as hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV) are of particular concern to the occupational health and safety of surgical staff. Infection transmission from the surgical team to the patient may also be of concern. [3] For these reasons it is important to have measures in place for infection control. Use of intact surgical gloves is one way of preventing the transmission of these infections. However, breached gloves allow potential exposure to infectious material, especially if there are cuts or abrasions present. Breached gloves not only indicate potential for mucocutaneous transmission but also promote the possible inoculation of blood from a needle stick injury. [1]

To prevent breaches of surgical gloves in theatre it has been suggested in the literature that using two pairs of gloves (double gloving) is effective in reducing transmission of infection to surgeons and operating room staff. Double gloving is thought to be superior to ‘single gloving’ as it has a greater resistance to withstand breaches and perforation, lowering the probability of puncture. [1] Furthermore, double gloving is also understood to provide a lower dose of inoculated infectious fluid during needle stick injuries. [2]

This article will examine whether ‘double gloving provides greater protection against infection transmission than single gloving during intraoperative glove perforation and needle stick injury’.

Why surgeons double glove

Double gloving reduces the amount of contact with the patient’s blood. Blood borne infection may be transferred when bodily fluids and blood are transferred between the surgical staff and a patient, exacerbated by pre-existing cuts or abrasions already present on the skin. One study revealed that pre-operatively, 17.4% of surgeons had skin abrasions on their hands. [1] Furthermore, 38-50% of practicing surgeons may not be adequately immunised against HBV to prevent infection. [13] It has been estimated in a study that double gloving reduced the rate of blood contamination of the hands from 13% in the single glove group to 2% in the double glove group. [14]

Double gloving is also effective at reducing the level of exposure to infectious material during a needle stick injury. The risk of acquiring an infection from percutaneous exposure after a needle stick injury is 0.3-0.4% for HIV, 6-30% for HBV and 3-10% for HCV. [9] The volume of bodily fluid transferred by the needle itself in a needle stick injury is a predictor of the possibility of infection, with lower volumes providing a  lower  viral  load.  [10]  A  recent  study  used  double  gloving  and single gloving techniques of the same collective thickness and glove material to determine the amount of contaminate transmitted during simulated needle stick injuries. The results supported that the double gloving technique provides greater protection, with lower levels of contaminate transmitted through the needle stick injury. [2] Hence, double gloving is likely to be effective at reducing the level exposure to contaminate on a needle and consequently may reduce the incidence of transmission of infection to surgical staff. Therefore double gloving reduces the exposure of infectious contaminate on a needle stick during an injury, and may help prevent establishment of an infection, improving occupational health and safety.

The risk of perforation when double gloving is lower than the risk of perforation compared to single gloving. Intact gloves prevent the transmission of infection and therefore are important in the control of infection and safety. An analysis of gloves post-operatively found that 20.8% of surgeons who had single gloved had perforations and exposure to potentially infectious material, but only 2.5% of surgeons that double gloved had tears in the inner and outer glove. [11] A systematic review, including 31 controlled trials, reported that there were significantly more perforations of the single glove than the innermost (closest to skin) of the double gloves (OR 4.10, 95% CI 3.30 – 5.09). [12] Additionally, using an indicator glove (coloured latex underneath a second glove) warns the surgical team of any perforations and allows a replacement of the outer glove, which reduces the probability of tearing both layers and exposure to infectious contaminate. [12] Therefore double gloving protects the surgical staff and the patient from any exposure to potentially infectious contaminate and improves occupational health in the operating room

Why surgeons may not double glove

On the contrary, it has been claimed that the use of ‘double gloving’ may  actually  compromise  manual  dexterity,  tactile  sensitivity  and 2-point discrimination of the surgeon, therefore reducing the ability and quality of the surgeon’s performance. [3] Another problem may be that a decrease of manual dexterity may increase the rate of needle stick injuries. Additionally there is poor acceptance among surgeons to double glove including a regular habit of single gloving, comfort, and low risk of transmission. Furthermore, some choose not to double glove because they feel there is a lack of evidence supporting its protection. [5]

Double gloving diminishes the hand sensibility and moving two-point discrimination of surgeons compared to single gloving, both of these being important for a surgeon to perform to the highest standards. Studies have demonstrated that double gloving does indeed have an effect on hand sensibility when evaluating pressure sensitivity, when compared to a single glove and no glove. Furthermore double gloving was found to impair moving two-point discrimination, but not static two-point discrimination, when compared to single gloving. [6] For this reason some surgeons prefer not to use two pairs of gloves as it can affect their surgical performance in the operating room.

Double  gloving  does  not  appear  to  reduce  manual  dexterity.  Of note, many surgeons that advocate single gloving argue that their dexterity decreases with fatigue. Manual dexterity is defined as the ability to move fingers skilfully, manipulate small objects rapidly and accurately. Some surgeons are also concerned that manual dexterity will be compromised if employing a double glove technique during an operation, and consequently may result in poor performance. However this has been challenged in the literature, which suggests there is no difference in dexterity whether single or double gloving techniques are employed. One study examined the knot tying abilities of individual surgeons wearing one and two layers of gloves and found that there was no statistically significant difference between them. [7] Another study found that there was no substantial impact on manual dexterity, measured by a Perdue Peg-board, in double, single and no glove groups. [3] Therefore the use of double gloving as protection does not impair the quality of the surgeon’s performance.

Double gloving does not increase the risk of injuries such as needle stick injuries. A decrease in the level of tactile sensibility and manual dexterity of the surgeon is thought to increase the frequency of needle stick injuries in theatre. However as stated previously, manual dexterity is not compromised by double gloving. Furthermore, a study found that there was no correlation with the frequency of actual injuries and glove perforations compared to the number of glove layers. [8] Double gloving is no more of a risk to injury than single gloving; hence there are no grounds for it to be an occupational hazard.

Double gloving is not universally accepted by surgeons due to a lack of information and misconceptions. A questionnaire completed by surgeons revealed that most (57%) do not double glove, and that the most common reason not to was because of a perceived loss of manual dexterity. After competing the survey, the participating surgeons were given evidence-based information on the potential occupational health benefits of double gloving and only 23% said they would change their practice. [5] Hence, the majority of surgeons do not accept double gloving even with current evidence and may be at unnecessary risk of  infection  transmission  opportunity.  Various  surgical  specialties have different views on double gloving.  Orthopaedic surgeons almost universally utilise double gloving technique due to the inherent risks of mechanical injury, [5] whereas plastic surgeons tend to have lower double gloving rates. [5] Furthermore the age of the surgeon appears to have an impact on double gloving rates with older surgeons often opting for single gloves.  Anecdotally most trainees now double glove.

Conclusion

In conclusion, ‘double gloving’ provides greater protection against infection transmission than ‘single gloving’ in relation to intraoperative glove perforation and needle stick injuries. The prevention of infection transmission between surgical staff and patients is an important aspect of the occupational health and safety of the operating room. There is clear evidence that double gloving reduces post-operative wound infection.  In fact this is much more effective than a 5-minute hand wash. However, it is also important to consider the performance of the surgical team with double gloves. Although manual dexterity is not compromised, hand sensibility and moving 2-point discrimination may be impaired whilst double gloving. Furthermore, even when presented with strong evidence for its beneficial use in practice, surgeons still prefer not to double glove. In summary, there is considerable literature that suggests the use of double gloving reduces the probability of infection transmission in the operating room, and because infection is an occupational danger, it is recommended that surgical staff double glove while performing operations.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

M Papageorgiou: papa0152@uni.flinders.edu.au

References

[1] Thomas S, Agarwal M, Mehta G. Intraoperative glove perforation – single versus double gloving in protection against skin contamination. Postgrad Med J. 2001; 77: 458-460

[2] Din SU, Tidley MG. Needlestick fluid transmission through surgical gloves of the same thickness. Occup Med. 2013; 64: 39-44

[3] Fry DE, Harris EW, Kohnke EN, Twomey CL. Influence of Double-Gloving on Manual Dexterity and Tactile Sensation of Surgeons. J Am Coll Surg. 2010; 210(3): 325-330

[4]  Buergler  JM,  Kim  R,  Thisted  RA,  Cohn  SJ,  Lichtor  JL,  Roizen  MF.  Risk  of  Human Immunodeficiency   Virus   in   Surgeons,   Anaesthesiologists   and   Medical   Students. Anaesthesia & Analgesia. 1992; 75: 118-124

[5] St. Germine RL, Hanson JH, de Gara CJ. Double gloving and practice attitudes among surgeons. Am J Surg. 2003; 185: 141-145

[6] Novak CB, Patterson MM, Mackinnon SE. Evaluation of Hand Sensibility with Single and

Double Latex Gloves. Plast Reconstr Surg. 1999 Jan; 103(1): 128-131

[7] Webb JM, Pentlow BD. Double gloving and surgical technique. Ann R Coll Surg Engl. 1993; 75: 291-292

[8] Jensen SL. Double gloving – electrical resistance and surgeons’ resistance. J Lancet. 2000; 355: 514-515

[9] Patz JA, Jodrey D. Occupational Health in Surgery: Risks Extending Beyond The Operating

Room. ANZ J Surg. 1995; 65(9): 627-629

[10] Bennet NT, Howard RJ. Quantity of blood inoculated in a needle stick injury from suture needles. J Am Coll Surg. 1994; 178: 107-110

[11] Gani JS, Anseline PF, Bissett RL. Efficacy of double versus single gloving in protecting the operating team. ANZ J Surg. 1990; 60(3): 171-175

[12] Tanner J, Parkinson T. Double gloving to reduce surgical cross-infection. Cochrane Database of Syst Rev. 2009; Issue 3. Art. No. CD003087

[13]  Barie  PS,  Dellinger  EP,  Dougherty  SH,  Fink  MP.  Assessment  of  Hepatitis  B  Virus Immunization Status Among North American Surgeons. Arch Surg. 1994 Jan; 129(1): 27-32

[14] Naver LPS, Gottrup F. Incidence of glove perforations in gastrointestinal surgery ad the protective effects of double gloves: a prospective, randomised controlled study. Eur J Surg 2000 May; 166(4): 293-295

The prescription of opioids is increasing worldwide, including in Australia. Consequently, opioid dependence – one of several harms associated with chronic opioid therapy – is now a growing concern. However, the risk factors for iatrogenic opioid dependence are not well understood in an Australian context. The available Australian evidence for these risks are reviewed and supplemented with data from the United States. Substance use disorder, mental disorder, pain severity and several demographic factors are associated with increased risk of opioid dependence. Factors originating within the health system, such as prescribed dose, chronicity, monitoring systems and physician attitudes may also contribute to patients developing dependence. Australian data represents a significant gap in the knowledge, and there is a need for good quality studies examining Australian populations.

Background

The rate of opioid prescribing both in Australia and worldwide has increased dramatically. [1-3] Opioid-like analgesic dispensing in Australia increased 53% between 2002 and 2009, with tramadol and oxycodone showing the largest increases. [1] This prescribing pattern is of concern since chronic opioid therapy is associated with multiple harms, including dependence and accidental overdose. [4,5] In the USA, prescription opioid-related deaths increased 68% between 1999 and 2003, [6] with the highest risk of death in patients who were prescribed high dose opioid therapy. [7] This trend has been mirrored to a lesser extent in Australia, with an increase in oxycodone-related deaths but not morphine-related deaths. [2] There is evidence that harms related to opioid therapy are increasing as a result of increased prescriptions. [2,8]

Iatrogenic dependence can be described as physician initiated inadvertent dependence. [9] The risk of iatrogenic opioid dependence is unknown and estimates differ greatly between acute and chronic settings. [4,10,11]  In  addition,  opioid  therapy  trials  tend  to  focus on efficacy and exclude individuals at high risk of dependence. [12] Despite these limitations, studies of patients taking chronic opioid therapy found a 35% lifetime prevalence of dependence. [4,13] As a consequence, iatrogenic opioid dependence is of concern for health professionals and balancing benefits with risk of dependence is a key clinical issue. [8,14,15]

The terminology used to define and describe the use of opioids is controversial. [16,17] There are two main diagnostic systems for the diagnosis of drug use disorders internationally. The DSM-V describes “substance use disorder” as a mild to severe state of chronically relapsing, compulsive drug taking. [18] The International Classification of Diseases (ICD-10) defines a “dependence syndrome” as a cluster of physiological, behavioural and cognitive phenomena in which the use of a substance takes on a much higher priority for a given individual than other behaviours that once had greater value. [19] Addiction is a term widely used by the general public, health professionals and in the literature. [17] It is described as a chronic condition characterised by behaviours such as compulsive use, continued use despite harm and craving. [16] It has been argued that the term “addiction” represents a variety of social and cultural constructs and is often value-laden. [17] For this reason, the term “dependence” is often preferred. [17] In this article, dependence will be used to describe a diagnosed drug use disorder. Readers should view dependence as distinct from physical dependence, tolerance, abuse and misuse, which are clarified in Table 1.

Guidelines for the prescription of opioids are conflicting, with confusion around safety and efficacy. [20,21] The United States has the highest rates of opioid use in the world and multiple reviews have examined the potential risk factors for addiction. [22,23] However, differences in prescribing, demographics and health system characteristics indicate that a review in an Australian context is of value. [1] This article summarises the available Australian evidence on the risk of iatrogenic opioid dependence, supplemented with studies from the US. Four major groups of patient risk factors are described: substance abuse disorder, mental disorder, pain severity and demographic factors. The role of dependence risk screening tools is briefly assessed.Finally, the contribution of specific health system and prescribing factors is discussed.

Methods

A literature search of publications relating to risk factors for prescription opioid dependence was undertaken. The databases PubMed, CINAHL and  Ovid  were searched  for  publications published  between 2004 and 2014. The search terms “Opioid OR Opiate” and “Dependence OR Addiction” and “Prescription” and “Risk” were used. This search yielded 205 publications. Additional articles were obtained from bibliographic searching. 39 relevant articles were included. 166 articles were excluded as they studied heroin use or focused on harms other than dependence, such as abuse or misuse.

Patient factors that increase risk

Substance use disorder

Despite substance abuse being a strong predictor for opioid dependence, Australian data on the relationship is lacking. Cross- sectional studies from the United States demonstrate a strong correlation  between  substance  abuse  disorder  and  chronic  opioid use. [24,25] In addition, evidence suggests that opioid dependence is more likely in those with a past or current substance abuse disorder. [4,8,26,27] This is consistent with a longitudinal study in which a diagnosis of non-opioid substance abuse was the strongest predictor of opioid dependence in those commencing opioid therapy. [15] Recent studies also demonstrate an association between smoking and opioid dependence, with one citing smoking as the most frequently reported risk factor in their cohort. [28,29] No Australian studies were found that  examined  this  relationship.  However,  the  Australian  National Drug Strategy Household Survey reported that 36% of recent users of opioids for non-medical reasons also used cannabis and 25% had used alcohol. [30] This data should be interpreted cautiously, as it does not reveal if the use was chronic or acute, or the reasons for use. At best it shows a tendency for opioids to be used with other psychoactive substances.

Mental disorders

Mental disorders increase the risk of iatrogenic opioid dependence. This is demonstrated by the fact that prescription opioid use is greater for patients with depression and anxiety. [25] Furthermore, these patients were prescribed opioids in higher doses and for longer durations than patients without a mental disorder. [24] Patients with mental disorders also have a higher incidence of chronic non-cancer pain. [24] Whether chronic pain is the cause or result of mental disorders is unknown; some evidence suggests the relationship is bidirectional. [24] Whether more opioids are prescribed to these patients on the basis of their higher reported pain remains to be established.

The outcomes of opioid treatment for patients with mental disorders are  not  well  characterised  as  these  patients  are  usually  excluded from clinical trials. [31] However, several studies show that mental disorders are significantly associated with opioid dependence. [4,8,15,26,27,29,32] Furthermore, having two comorbid mental disorders increases the risk of addiction compared to a single mental disorder. [8] One study found a correlation between PTSD severity and opioid use, suggesting that severity of symptoms may also be implicated. [33]

Despite the increased risk of opioid dependence with mental disorders, one longitudinal study of fifteen thousand veterans with chronic prescription opioid use in the United States showed that only 3% of pain patients with comorbid mental disorders progressed to opioid abuse or dependence. [15] This highlights that the presence of a mental disorder alone cannot predict a patient’s risk of developing dependence to a prescribed opioid. There is a lack of Australian data establishing a link between mental disorders and opioid dependence.

Patient demographics

There are a number of demographic factors that may increase the risk of a patient developing opioid dependence. Studies conducted in the US have identified younger age as a strong predictor of opioid dependence, with individuals under 65 showing increased risk. [4,8,15] In Australia, the National Drug Strategy Household Survey (NDSHS) found that use of opioids for non-medical purposes was highest in persons ages 20-29. [30] As in other substance use disorders, men are more likely to develop opioid abuse or dependence than women. [8,15,26] This is consistent with NDSHS, which found that men were more likely to use pharmaceuticals for non-medical purposes in their lifetime. [30] Several  other  factors such as living rurally and early age of exposure to nicotine, alcohol and other drugs are significantly associated with opioid dependence. [27] In addition, a family history of substance use disorder and time spent in jail may increase the risk. [26] Being divorced, single or separated and childhood emotional trauma are also associated with opioid dependence. [4,15] It is possible that these factors interrelate and are thus more likely to occur together, compounding the risk.

A recent Australian study analysed data from the Bettering the Evaluation and Care of Health (BEACH) program, which collects data on interactions patient consultations in general practice. It found that Commonwealth Concession Card holders had a significantly higher rate of opioid prescribing compared to other patients. [34] This data poses an interesting question as to why opioid prescribing in this population is higher. Possibilities include increased willingness of doctors to prescribe and lack of access to alternative treatments such as physiotherapy.

Pain severity

The severity of a patient’s pain may contribute to opioid addiction. [35] Persistent use of opioids for chronic pain is associated with severe or very severe reported pain. [36] In addition, opioid-dependent individuals show a greater degree of pain-related limitation and greater pain severity. [4,26] This may be because addiction lowers the pain tolerance, or that a lower pain threshold confers an increased risk of addiction. [26,37] Alternatively, people experiencing greater pain severity may simply be prescribed higher doses of opioids. This could also be due to opioid-induced hyperalgesia, a state of nociceptive sensitization caused by exposure to opioids. [38] This can be mistaken for tolerance, which may result in a higher dose of opioids prescribed and thus an increased risk of addiction. No Australian studies were found examining the relationship between pain severity and increased risk of addiction.

Screening for risk

Ultimately, established risk factors should be used to create reliable screening strategies. While that is considered good practice, there is no one screening procedure that can identify chronic pain patients at risk of opioid dependence. [21,22] A common issue is the overlap of behaviours also seen in patients with undertreated pain, such as demand  for  higher  dose  medications,  and  taking  medication  in  a way other than prescribed (defined as misuse). [22] This is further complicated by the fact that established risk factors have been found to be poorly associated with aberrant drug behaviours. [29]

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R, https://www.painedu.org/soapp.asp) tool is a self- administered 24-item tool assessing common risk factors for opioid misuse, abuse and dependence. [39] The items assess mood, attitudes towards treatment, personality traits and substance use disorder. [39] A recent study found the SOAPP score to be the strongest predictor of dependence in a cohort of patients using over the counter and prescription painkillers. [40] In addition, Butler et.al found the SOAPP-R to be reliable and valid across two different chronic pain patient populations. [39,41] However, the usefulness of SOAPP-R in a primary health care setting remains to be determined. [39]

The American Society of Interventional Pain Physicians does not recommend the use of formal dependence risk screening tools. [21] In their recent guidelines for responsible opioid prescribing, they suggest that risk stratification can be achieved through a comprehensive physician’s assessment. [21] This should include psychosocial history, functional status, psychological evaluation, substance abuse history and physical exam. [21]

Health system factors contribute to risk

In  addition  to  patient  factors,  there  are  multiple  health  system factors  that  contribute  to  prescription  opioid  dependence.  These are prescribing dose, duration of therapy, monitoring systems and physician attitudes.

Few studies have examined the relationship between dose and duration of therapy and risk of dependence. However, in a large cross-section study of individuals with a new episode of chronic non-cancer pain, those prescribed high morphine equivalent dose (120 mg), chronic (>90 days) opioid therapy were 50 times more likely to develop dependence than those on low dose acute therapy. [8] This is consistent with a recent study, which found the odds ratio for developing dependence with high dose, chronic opioid use was 122.45. [11] While the rate of high dose chronic opioid prescription in this sample was relatively low (0.1% of chronic pain patients), it represents a number needed to harm of 16.7. [8] Given the significant negative consequences of opioid dependence this number needed to harm may be unacceptable. Multiple studies found that duration of opioid therapy was more important than daily dose in determining risk of dependence. [8,11,42] Indeed, data suggests that other risk factors such as younger age and comorbid mental disorders contributed less to the risk than dose and chronicity alone. [8] This is supported by another study which found that greater than 211 days of prescribed opioids was more predictive of dependence than 90-211 days. [15] Importantly, this also suggests that the association between risk and chronicity is a linear relationship. In Australia stronger formulations account for the minority of opioids prescribed. [2] However, more research into the relationship between opioid dose, chronicity and dependence is required.

One of the goals of responsible opioid prescribing is adequate monitoring, due to the consequences of duration mentioned above. [5,21] Existing monitoring systems in Australia cannot track opioid prescriptions and supply down to the individual patient level. [5] The Pharmaceutical Benefit Schedule (PBS) data set generates a Medicare file,  which  can  potentially  identify  patients  misusing  opioids.  [5]

However, no information is included in the PBS record if a patient pays the entire cost of the medication. [5] Lack of access to comprehensive information can contribute to inappropriate prescribing. [43] Thus, a real-time prescription coordination program making use of technology would be greatly beneficial. [43]

Physician attitudes towards opioid analgesics may also profoundly impact on treatment. [14] In a mailed survey to General Practitioners in Ontario, GPs who did not believe many patients became addicted to opioids also prescribed more opioids. [14] Furthermore, over 10% of GP’s were not confident in their skills prescribing opioids. [14]. Surveys of Australian physicians studying attitudes to the use of opioids are required. Regardless of the attitude of physicians towards opioid prescription, there remains a responsibility to manage patients’ pain effectively. It is well recognised that this poses an ethical dilemma to the treating physician and involves a careful balance of risk and benefit. [9, 44] Several guidelines are available to clinicians to increase their confidence in prescribing opiate analgesics, including the RACP [45] and Hunter New England guidelines. [46]

Conclusion

It is apparent that individuals with highest risk of iatrogenic dependence will possess a constellation of risk factors. A combination of young age, depression, psychotropic medications and pain impairment combined with  substance  use  history  predicted  greatest  increased  risk  for opioid dependence. [4] However, methods for screening risk remain unreliable, compounded by a lack of universal guidelines to guide practice. In addition, high dose, chronicity, monitoring systems and physician attitudes may also increase the risk of dependence in the population. Thus far, Australian studies into opioid use have described trends in prescribing practices. Studies examining risk factors for iatrogenic opioid dependence represent a significant gap in the knowledge. Further research is likely to help guide clinicians to make better-informed decisions around opioid prescribing.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

H Hartman: hannah.hartman@my.jcu.edu.au

References

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[24] Edlund MJ, Martin BC, Devries A, Fan M-Y, Braden JB, Sullivan MD. Trends in use of opioids for chronic non-cancer pain among individuals with mental health and substance use disorders: the TROUP study. Clin J Pain. 2010;26(1):1-8.

[25] Sullivan MD, Edlund MJ, Zhang L, Unützer J, Wells KB. Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med. 2006;166(19):2087-93.

[26] Liebschutz JM, Saitz R, Weiss RD, Averbuch T, Schwartz S, Meltzer EC, et al. Clinical factors associated with prescription drug use disorder in urban primary care patients with chronic pain. J Pain. 2010;11(11):1047-55.

[27]  Cicero  TJ,  Lynskey  M,  Todorov  A,  Inciardi  JA,  Surratt  HL.  Co-morbid  pain  and psychopathology in males and females admitted to treatment for opioid analgesic abuse. Pain. 2008;139(1):127-35.

[28] Zale EL, Dorfman ML, Hooten WM, Warner DO, Zvolensky MJ, Ditre JW. Tobacco smoking, nicotine dependence, and patterns of prescription opioid misuse: results from a nationally representative sample. Nicotine Tob Res. 2014 Oct 25.

[29] Layton D, Osborne V, Al-Shukri M, Shakir SAW. Indicators of drug-seeking aberrant behaviours: the feasibility of use in observational post-marketing cohort studies for risk management. Drug Safety. 2014;37(8):639-50.

[30] Australian Institute of Health and Welfare. 2007 National Drug Strategy Household Survery: detailed findings Canberra AIHW, 2008.

[31] Kalso E, Allan L, Dellemijn PL, Faura CC, Ilias WK, Jensen TS, et al. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain. 2003;7(5):381-6.

[32] Mackesy-Amiti ME, Donenberg GR, Ouellet LJ. Prescription opioid misuse and mental health among young injection drug users. Am J Drug Alcohol Abuse. 2015;41(1):100-6.

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Glycaemic control around the time of surgery is a critical part of surgical care in diabetic patients. There is a high prevalence of diabetes mellitus worldwide, and the disease is becoming more common in both medical and surgical patients. Even in patients without diabetes, surgery disrupts usual diabetic management and glucose homeostasis, often resulting in perioperative hyperglycaemia. Hyperglycaemia has been associated with increased postoperative mortality and morbidity, as well as worse surgical outcomes in both cardiac and non-cardiac surgery. Published evidence suggests that outcomes can be improved in perioperative patients by closer management and control of glucose.

Despite early studies in the intensive care unit (ICU) setting, subsequent trials were not able to demonstrate improved outcomes with the use of intensive insulin therapy, which aimed for stricter glycaemic control (4.5–6.0 mmol/L) that was closer to physiological ranges. Whilst the optimal blood glucose concentrations are still unknown, current literature supports the use of moderately strict glycaemic control (5.0–10.0 mmol/L) via a basal-bolus insulin regimen, so as to balance the risks of inducing hypoglycaemia with the benefits of avoiding hyperglycaemia.

Introduction

Diabetes mellitus is a highly prevalent group of metabolic diseases worldwide, and a significant proportion of surgical patients are diabetic. [1] An important component of diabetic perioperative management is glucose control, as glucose homeostasis is easily disrupted during periods of physical stress and illness. Recent studies have shown that hyperglycaemia during surgery is not a benign condition like it was once considered to be, and that treatment results in reduced mortality and morbidity. This literature review will focus on the current understandings of the effects of diabetes, how hyperglycaemia can affect clinical outcomes in the surgical setting, and the present consensus on the management of blood glucose in diabetic patients perioperatively.

Methods

This literature review is constructed as an unsystematic narrative review. The search for current literature was performed through the Ovid Medline database, the PubMed database, and the Cochrane Library. The following search terms and their related terms were used: perioperative glycaemic control, perioperative hyperglycaemic, perioperative diabetic management, intensive insulin therapy, sliding-scale insulin, basal bolus. The articles evaluated were limited to publication between January 1^st, 2000 and March 1^st, 2015. Articles published were restricted to the English language and to the adult surgical population. Given the breadth of literature on the topic, only major influential studies were selected for review. Studies performed on highly specific populations were excluded. Relevant retrospective observational studies, RCTs, and meta-analyses were included for analysis. Published review articles and editorials were examined for major influential studies. Any relevant in-text citations were also considered for inclusion. In total, forty-seven (n = 47) articles were selected for full text retrieval after abstract screening.

Background

Epidemiology

According to the Australian Institute of Health and Welfare, approximately 900 000 Australians have diabetes. [2] However, it has been estimated that up to half of all cases remain undiagnosed. [3] Similarly, the International Diabetes Federation estimates that diabetes prevalence in the adult Australian community is 9.99%. [4] Type 2 diabetes is the most common variant, accounting for 85-90% of all diabetics. [5] An audit across eleven hospitals in metropolitan Melbourne indicated that 24.7% of all inpatients had diabetes, with prevalence ranging from 15.7% to 35.1% in different hospitals. [6] Given the predicted exponential rise in obesity over the next decade and the current trend of an ageing population, projections suggest that 3.3 million Australians will have type 2 diabetes by 2031. [7]

Pathophysiology of diabetes

Although pathogenesis differs for the various forms of diabetes mellitus, hyperglycaemia is an underlying mechanism by which the disease can cause long-term complications. Diabetes is characterised by a lack of, or reduced effectiveness of, endogenous insulin, which then results in elevated fasting blood glucose concentrations and an inadequate response to glucose loads. Glucose homeostasis is tightly regulated, with normal blood glucose values being maintained within a narrow range between 4.4–7.8 mmol/L. [8] Chronic concentrations above 7.0 mmol/L are capable of producing end organ damage. [9]

Left untreated, diabetes mellitus is a disease associated with acute and chronic organ dysfunction and failure. Persistent hyperglycaemia leads to morbidity mainly through damaging medium and large-sized arteries (macrovascular disease) and causing capillary dysfunction in end organs (microvascular disease). Macrovascular disease increases the risk of developing ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease, while microvascular disease results in diabetic retinopathy, nephropathy, and neuropathy. [10]

 Diabetes and surgery

Given the high prevalence of diabetes seen in the community and hospitals, we can expect a significant proportion of those who present for surgery to have the diagnosis. Diabetic complications such as ischaemic heart disease and diabetic eye disease also increase the likelihood of requiring surgical interventions, and it has been estimated that 50% of all diabetic patients will undergo surgery at some stage. [11] The prevalence of cardiovascular diseases, including hypertension, coronary artery disease and stroke, are two to four times higher in diabetic patients, compared to non-diabetics. [12] Diabetes is also the leading cause of end-stage renal failure, adult-onset blindness, and non-traumatic lower extremity amputations.

In addition, diabetes puts patients at a higher perioperative risk for adverse outcomes when compared to non-diabetics. Mortality has been reported to be up to 50% higher than that of the non-diabetic population. [13] Diabetic patients are also more likely to develop postoperative infections, arrhythmias, acute renal failure, ileus, stroke, and myocardial ischaemia. [14-16] Due to the wide range of complications that can occur, diabetic patients have a 45% longer length of stay postoperatively, with higher health care resource utilisation, compared with non-diabetic patients. [17]

Diabetic patients are prone to dysregulation of glucose homeostasis, especially during surgical stress or critical illness. Since most surgical patients will need to fast prior to surgery, there is often considerable disruption to their usual diabetes management routine. About 20% of elective surgical patients demonstrate impaired fasting blood glucose concentrations. [1] Other factors such as postoperative infections and emesis can all lead to labile blood glucose concentrations. Meanwhile, both surgery and anaesthesia produce a hypermetabolic stress response by elevating the levels of stress hormones and inflammatory cytokines such as catecholamines, cortisol, growth hormone, and TNF-α. [18] These hormones increase blood glucose concentrations by upregulating hepatic gluconeogenesis and glycogenolysis, as well as exacerbate insulin resistance and decrease insulin secretion. [18]

Discussion

Effects of perioperative hyperglycaemia and benefits of glycaemic control

Hyperglycaemia is a prevalent phenomenon in surgical patients. One study found that 40% of non-cardiac surgery patients had a blood glucose concentration >7.8 mmol/L, with 25% of those patients having a blood glucose concentration >10.0 mmol/L. [19] Perioperative hyperglycaemia was once considered to be a beneficial physiological adaptive response to surgery and critical illness, intended to supply energy to vital organs. This is now largely known to be untrue, with observational studies and randomised controlled trials indicating that improvement in glycaemic control results in lower morbidity and mortality, shorter length of stay, and fewer complications such as nosocomial infections, postoperatively. Outside of surgery, hyperglycaemia has also been associated with worse outcomes in critically ill, hospitalised patients. [20] Patients who are hyperglycaemic following a stroke demonstrate worse functional recovery and higher mortality compared to patients with normal glycaemic control. [21]

Retrospective observational studies

An observational study on patients undergoing non-cardiac surgery by Frisch et al. demonstrated that perioperative hyperglycaemia is associated with significantly increased risk of pneumonia, sepsis, urinary tract infection, skin infection, acute renal failure and death during the postoperative period. [19] Ramos et al. found a correlation between blood glucose concentrations and the rate of postoperative infection and length of hospital stay in general and vascular surgical patients. The study observed that every 2.2 mmol/L rise in postoperative blood glucose concentration above 6.1 mmol/L resulted in an increase in the infection rate by 30%. [22] In cardiac surgery, Gandhi et al. observed that intraoperative hyperglycaemia is an independent risk factor for post-operative complications, including death. [23] Schmeltz et al. demonstrated that the use of a combination of IV and subcutaneous insulin to improve glucose control in cardiac surgery reduced the mortality and infection rates among diabetic patients to those of non-diabetic patients. [24]

Hyperglycaemia has been shown to be the significant risk factor for perioperative morbidity and mortality, rather than diabetes itself. A retrospective cohort study based on 11,633 patients by Kwon et al. found that perioperative hyperglycaemia was associated with a near doubling in the risk of infection, mortality, and operative complications in both diabetic and non-diabetic general surgical patients. [25] A retrospective study by Doenst et al. concluded that a high peak blood glucose concentration during cardiopulmonary bypass was an independent risk factor for death and morbidity in diabetic patients. [26]

Prospective randomised controlled trials

A prospective randomised controlled study of surgical ICU patients by Van den Berghe et al. in 2001 (first Leuven study) demonstrated significantly reduced morbidity and mortality in critically ill patients when the blood glucose concentrations were maintained between 4.4–6.1 mmol/L via an intravenous insulin infusion. [27] In another randomised prospective study by Lazar et al., 141 diabetic cardiac surgery patients were assigned to either moderately tight glycaemic control (6.9–11.1 mmol/L) with a glucose-insulin-potassium (GIK) regimen, or to standard therapy (<13.9 mmol/L) using intermittent subcutaneous insulin. [28] The GIK patients had a lower incidence of atrial fibrillation and a shorter postoperative length of stay, compared to patients receiving standard therapy. The intervention was commenced prior to anaesthesia, and only continued for 12 hours postoperatively. Interestingly, the GIK patients were able to demonstrate a survival advantage two years postoperatively, with decreased episodes of recurrent myocardial ischaemia and fewer recurrent wound infections. This suggests that moderately tight control even for a brief period can make substantial differences to long-term outcomes.

The Diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study by Malmberg et al., which looked at 620 diabetic patients post-acute myocardial infarction, reported a 29% reduction in the 1-year mortality rate in patients who were randomised to receive intensive glucose management (mean blood glucose concentration of 9.6 mmol/L at 24 hours) when compared to patients assigned to receive conventional treatment (mean blood glucose concentration of 11.7 mmol/L at 24 hours). [29]

The question of whether the insulin therapy itself or the treatment of hyperglycaemia resulted in benefit has not been fully answered, as the metabolic and cellular actions of insulin may contribute to the beneficial outcomes. Insulin therapy has been shown to improve dyslipidaemias and prevent endothelial dysfunction and hypercoagulability in critically ill patients. [30] Treating a patient with insulin causes arterial vasodilation and capillary recruitment, via activation of the nitric oxide pathway and improves myocardial perfusion. [31] However, the first Leuven study found that the positive effects of intensive insulin therapy were related to the lower blood glucose concentrations, rather than insulin doses. [27]

Intensive versus conventional glycaemic control

Beyond avoidance of marked hyperglycaemia and hypoglycaemia, the optimal perioperative glucose targets are unclear. Conventional glycaemic control targets blood glucose concentrations <10.0 mmol/L, and there has been considerable controversy over the safety and efficacy of intensive insulin therapy (IIT), which aimed at a much lower and narrower concentration between 4.5–6.0 mmol/L. Despite early results, which suggested decreased mortality and other advantages of intensive glucose control, [27] later investigations found no benefits or increased mortality when hyperglycaemia was aggressively treated with insulin. [32-33] The current consensus is that intensive control does not actually confer any benefits with regards to mortality, but increases the risk for hypoglycaemia, which is a potentially life-threatening complication. [34] The brain is an obligate glucose metaboliser, hence neurons are particularly vulnerable to low blood glucose concentrations. Even brief periods of hypoglycaemia (i.e. blood glucose concentration <2.2 mmol/L) can induce arrhythmias, cardiac events, and brain injury. [35]

The first Leuven study published in 2001 by Van den Berghe et al. demonstrated significant reductions in morbidity and mortality (by 34%) in over 1500 surgical ICU patients with tight glycaemic control (4.4–6.1 mmol/L) when compared to conventional control (<10–11.1 mmol/L). [27] Intensive insulin therapy (IIT) was also shown to decrease the duration of mechanical ventilation and ICU length of stay. However, there were many study limitations that could have affected the validity of the results. Many subsequent randomised controlled trials and meta-analyses that were published contrasted with the initial Leuven study, finding no benefit when IIT was used for glycaemic control, as well as a significantly higher risk of hypoglycaemia. [32-34]

A second Leuven study published in 2006 by Van den Berghe et al. was a randomised controlled trial comparing IIT and conventional therapy in 1200 medical ICU patients, and it did not demonstrate any mortality benefit with intensive insulin therapy, while observing more prevalent hypoglycaemic events in the treatment group. [32] Kujik et al. observed that intensive glucose control in the perioperative period has no clear benefit on short-term mortality in patients undergoing major vascular surgery, and recommended that moderate tight glucose control be regarded as the safest and most efficient approach to patients undergoing surgery. [36] Duncan et al. found that in cardiac surgery, although severe intraoperative hyperglycaemia (>11.1 mmol/L) was associated with higher risk of mortality and morbidity, blood glucose concentrations closest to normoglycaemia (average of 7.78 mmol/L or less) were also associated with increased mortality and morbidity. [37] In fact, the lowest risk of adverse outcomes was observed in the range between 7.8–9.4 mmol/L, suggesting that mild hyperglycaemia was better tolerated than strict control. The association of tight blood glucose control with worse outcomes was observable despite rare episodes of hypoglycaemia, which suggests that there are factors other than hypoglycaemia that could contribute to the poor outcomes of intensive glucose control.

The largest and most definitive study to date is the Normoglycaemia in Intensive Care Evaluation – Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, which was a multicentre, international, randomised controlled trial aimed at comparing intensive insulin therapy (4.5–6 mmol/L) with conventional treatment (8–10 mmol/L). [33] The study reported a higher 28-day and 90-day mortality rate in surgical ICU patients who received IIT, with significantly more severe hypoglycaemia in those patients. The authors were not able to demonstrate a difference in hospital or ICU length of stay, length of mechanical ventilation, or the need for renal replacement. In contrast to the initial Leuven study, mortality rates were higher in the IIT group (27.5% vs 24.9%). The NICE-SUGAR trial also reaffirmed a higher incidence of hypoglycaemia in the IIT group.

A Cochrane meta-analysis of 12 randomised trials (1403 patients with diabetes) comparing intensive (blood glucose concentration of <6.7 or <8.3 mmol/L) versus conventional (variable) glycaemic control by Buchleitner et al. also found that intensive glycaemic control has no significant effect on infectious complications, cardiovascular events, or mortality, except for increasing the number of hypoglycaemic episodes. [34] Given the current data available from randomised controlled clinical trials, the authors concluded that intensive glycaemic control protocols with near-normal blood glucose targets cannot be generally recommended for patients with diabetes undergoing surgery.

Basal-bolus versus sliding scale insulin

Insulin is generally the preferred method of treatment for inpatients as it is an effective medication for immediate control of hyperglycaemia in the hospital setting. The dose can be titrated more rapidly than that of oral hypoglycaemic agents, and it does not have a dose ceiling. Insulin can be delivered either subcutaneously or intravenously as a continuous infusion, and the use of sliding-scale insulin (SSI) has traditionally been the mainstay of hyperglycaemia therapy. However, recent studies have shown that the use of SSI alone is insufficient in providing adequate glycaemic control, and that a combination of basal and supplemental insulin is a more effective approach.

The combined use of basal insulin (i.e., intermediate- to long-acting insulin) together with short- or rapid-acting insulin before meals is able to better mimic physiological patterns of glucose control. The RABBIT 2–Medical trial by Umpierrez et al. demonstrated an improvement in glycaemic control with basal-bolus insulin in 130 diabetic insulin-naïve medical patients, with no increase in the number of hypoglycaemic events. [38] The subsequent RABBIT 2–Surgical trial, which is a multi-institutional randomised trial that looked at 211 type 2 diabetic general surgical patients, also found improved glycaemic control and reduced hospital complications with the basal-bolus regimen when compared to the sliding-scale insulin regimen. [39] The most recent evidence suggests that both medical and surgical type 2 diabetic patients with poor glycaemic control (blood glucose concentration >10 mmol/L or HbA1c >7.5%) should be treated with the basal-bolus insulin regimen. [40]

Current Recommendations

Figure 1. Recommended perioperative BSL targets.

Given that studies have failed to show a benefit and some even show increased mortality with intensive insulin therapy, the management of glucose concentrations has undergone drastic changes in the past decade. Current recommendations from the UK, US, and Australia all recommend a similar range of blood glucose concentrations (Figure 1). Most guidelines tolerate mild hyperglycaemia as it reduces the potential for developing hypoglycaemia. Insulin therapy in both general medical and surgical settings should consist of a mixture of basal, prandial, and supplemental insulin (basal-bolus), instead of the sliding-scale regimen. However, differences in these recommendations indicate that the most optimal blood glucose concentrations are still unknown.

Preoperative insulin therapy should focus on obtaining good glycaemic control, while avoiding episodes of hypoglycaemia. The Endocrine Society’s Clinical Guidelines recommend a fasting blood glucose concentration of <7.8 mmol/l and a random blood glucose concentration of <10.0 mmol/l for the majority of hospitalised patients with non-critical illness. [41] For avoidance of hypoglycaemia, therapy should be reassessed when blood glucose concentration falls below 5.6 mmol/L. Similarly, the National Health Service Diabetes Guideline published in 2012 by Dhatariya et al. recommends blood glucose concentrations between 6.0–10.0 mmol/L, while accepting 4.0–12.0 mmol/L. [42] The Australian Diabetes Society currently recommends a blood glucose target of 5.0–10.0 mmol/L in both the ICU and non-ICU settings. [43] The American Diabetes Association and the American Association of Clinical Endocrinologists currently recommend commencing insulin therapy for critically ill patients with persistent hyperglycaemia (>10.0 mmol/L), and to aim for a blood glucose target range between 7.8–10.0 mmol/L, [44] while the American College of Physicians recommends 7.8–11.1 mmol/L  for critically ill patients. [45]

The mainstay of type 2 diabetes therapy is oral hypoglycaemic agents, such as metformin and sulfonylureas. Most guidelines suggest withholding oral anti-diabetic agents and non-insulin injectable medications on the day of surgery but not before. For major surgeries, metformin should be withheld for at least 24 hours. This is because oral diabetic medications can potentially produce hypoglycaemia during the fasting period prior to surgery, as well as systemic effects that may affect postoperative outcomes. For example, sulfonylureas can interfere with the opening of cardiac K_ATP channels, which increases the risk for myocardial ischaemic injury. [46] Metformin can potentially induce lactic acidosis if renal function is impaired. [47] However, ceasing anti-diabetic therapy too early may compromise glucose control, hence short- or medium-duration insulin should be used to treat acute hyperglycaemia during the operative period. Oral hypoglycaemic agents should not be restarted until adequate and regular oral intake is resumed.

The majority of patients receiving insulin therapy should use a basal-bolus insulin schedule. The long-acting agents are aimed at providing a steady, basal level of insulin while the shorter-acting bolus insulin is used to counter acute increases in blood glucose. It is important to note that not only type 1 diabetics, but all insulin dependent patients, will require insulin perioperatively, despite their fasting status. This is because these patients are insulin deficient and require consistent basal insulin replacement to prevent unchecked gluconeogenesis and ketosis.

Conclusion

Hyperglycaemia has been shown to produce deleterious effects in multiple body systems, both acutely and chronically. Studies indicate that adequate glycaemic control during the perioperative period is beneficial for both short-term and long-term surgical outcomes. While the optimal target blood glucose range is still unclear, the literature supports the use of moderately strict glycaemic control for the management of hyperglycaemia in surgical patients. The use of basal-bolus insulin is preferred over the more traditional sliding-scale insulin for its efficacy and safety. With the current trend of rising diabetes incidence in Australia, maintaining good glycaemic control during the perioperative period will become an increasingly important challenge faced by health professionals.

Acknowledgements

Professor Kate Leslie, Head of Research, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia for her critical review and helpful comments and suggestions.

Conflict of interest

None declared.

Correspondence

A Zhang: zazhang@student.unimelb.edu.au

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[33] Investigators N-SS, Finfer S, Chittock DR, Su SY, Blair D, Foster D, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97.

[34] Buchleitner AM, Martinez-Alonso M, Hernandez M, Sola I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev. 2012;9:CD007315.

[35] Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6):1389-94.

[36] van Kuijk JP, Schouten O, Flu WJ, den Uil CA, Bax JJ, Poldermans D. Perioperative blood glucose monitoring and control in major vascular surgery patients. Eur J Vasc Endovasc Surg. 2009;38(5):627-34.

[37] Duncan AE, Abd-Elsayed A, Maheshwari A, Xu M, Soltesz E, Koch CG. Role of intraoperative and postoperative blood glucose concentrations in predicting outcomes after cardiac surgery. Anesthesiology. 2010;112(4):860-71.

[38] Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007;30(9):2181-6.

[39] Umpierrez GE, Smiley D, Jacobs S, Peng L, Temponi A, Mulligan P, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care. 2011;34(2):256-61.

[40] Umpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, et al. Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial. Diabetes Care. 2013;36(8):2169-74.

[41] Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. 
Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(1):16-38.

[42] Dhatariya K, Levy N, Kilvert A, Watson B, Cousins D, Flanagan D, et al. NHS Diabetes guideline for the perioperative management of the adult patient with diabetes. Diabet Med. 2012;29(4):420-33.

[43] Australian Diabetes Society. Peri-operative Diabetes Management Guidelines. 2012. [Cited 10 September 2014]. Available from: https://diabetessociety.com.au/documents/PerioperativeDiabetesManagementGuidelinesFINALCleanJuly2012.pdf

[44] Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119-31.

[45] Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-7.

[46] Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR, Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999;33(1):119-24.

[47] Mercker SK, Maier C, Neumann G, Wulf H. Lactic acidosis as a serious perioperative complication of antidiabetic biguanide medication with metformin. Anesthesiology. 1997;87(4):1003-5.

Central sensitisation is the process whereby nociceptive inputs trigger increased excitability and synaptic efficiency of central nociceptive pathways, and is a key process in the development of chronic postoperative pain. Pre-emptive analgesia, whereby analgesia is given prior to surgical incision, has previously been advocated as a method of decreasing the process of central sensitisation and its clinical consequences – namely hyperalgesia, allodynia and chronic post-surgical pain (CPSP). A systematic review of pre-emptive analgesia has demonstrated positive studies existing only for the modalities of epidural analgesia, NSAIDs and local anaesthetic wound infiltration. [1]

A shift towards preventive analgesia has been advocated, a strategy in which analgesia is given for as long as the sensitising stimulus remains present. [2-6][Vadivelu, 2014 #8] This may include the preoperative, intraoperative and post-operative periods. Systematic reviews evaluating preventive analgesia have returned a greater proportion of favourable trials. In particular, NMDA antagonists have been shown to be promising in the preventive setting, and have been observed to decrease perioperative pain and post-operative analgesic consumption. [7]

The concept of pre-emptive analgesia, where the main focus is on the timing of the intervention with respect to incision, should be replaced with the broader approach of preventive analgesia. Appropriate analgesia should be provided for as long as a sensitising stimulus remains present. Further research should focus on determining the analgesic regimens that most effectively decrease the clinical consequences of central sensitisation, including hyperalgesia, allodynia and CPSP.

 Background

The relationship between intra-operative tissue damage and the amplification of post-operative pain was first described by Crile almost a century ago, in a process now referred to as central sensitization. [2] The concept of pre-emptive analgesia was proposed as a means of decreasing changes occurring in nociceptive pathways, resulting in minimisation of post-operative pain and analgesic consumption, as well as a decreased incidence of CPSP. [8] This approach involves the administration of analgesia prior to surgical incision. While this has been shown to effectively decrease dorsal horn changes associated with central sensitisation, clinical evidence has been equivocal. [9]

More recently, preventive analgesia has been proposed as a more effective method of modulating central sensitisation. Preventive analgesia focuses on blocking any nociceptive signals arriving at the dorsal horn by providing analgesia for as long as sensitising stimuli persist. [4] Interventions may extend from the pre-operative period until final wound healing, and are not confined to the pre-incisional period as for the pre-emptive approach. Preventive analgesia is defined in Acute Pain Management: Scientific Evidence as the “persistence of analgesic treatment efficacy beyond its expected duration”. [9, p.13] This approach has been found to be a more effective strategy for decreasing post-operative pain and analgesic consumption than a strictly pre-emptive approach. [2,6,9] Perioperative pain management should emphasise continuous analgesia for as long as a noxious stimulus is present, rather than focus on the timing of an intervention.

Central sensitisation

The surgical process produces nociceptive signals via several mechanisms, including skin incision, tissue damage and post-operative inflammation. Repeated afferent noxious signals at the level of the dorsal horn can induce neuronal hypersensitivity, mainly from alterations to glutamate receptors and ion channels. [4] Alterations at the dorsal horn include increased membrane excitability, greater synaptic efficiency and decreased activity of inhibitory interneurons. [10] This produces the clinical consequences of central sensitisation, namely hyperalgesia and allodynia. It may also lead to the development of chronic post-surgical pain (CPSP), which affects 10-50% of patients post-surgically, and is severe in 2-10% of these cases. [4]

While general anaesthesia attenuates the transmission of noxious afferent signals to the spinal cord, it does not completely block it. [3] Systemic opioids may similarly fail to provide sufficient blockade at the dorsal horn to prevent central sensitisation. Hence, while the patient is unconscious during the procedure, the stimuli necessary for central sensitisation persist, leading to increased post-surgical pain with greater analgesic consumption, and possibly increasing the chance of developing CPSP.

N-methyl-d-aspartate (NMDA) has been implicated as a key substance in the development of central sensitisation. [10] There has been increasing interest in the role of NMDA antagonists such as ketamine, dextromethorphan and magnesium as agents in providing preventive analgesia. Possible mechanisms include direct effects at the dorsal horn, and by reduction of the development of acute opioid tolerance. [7]

Search strategy

MEDLINE was searched through to June 2014 using the following search criteria: preventive OR pre-emptive OR preemptive AND analgesia. 1166 results were returned. Studies qualifying as level one evidence by NHMRC evidence hierarchy were included in the review (systematic reviews and meta-analyses). 1155 results were excluded from the review as they did not qualify as level one evidence. Eleven studies were identified for inclusion.

 Clinical evidence – pre-emptive analgesia

Clinical studies evaluating pre-emptive analgesia have shared several methodological flaws. Most often, this is due to a misunderstanding in what constitutes pre-emptive analgesia, with many studies instituting direct analgesia instead. There is also difficulty in establishing a valid control group, as all study participants must receive post-operative analgesia for ethical reasons. The administration of post-operative analgesia may attenuate the central sensitisation that occurs secondary to post-surgical inflammation, thus biasing the control group towards favourable outcomes.

Moiniche, Kehlet and Dahl reviewed double-blind, randomised, controlled trials (RCTs) which evaluated pre-incisional versus post-incisional analgesia, and the effect on postoperative pain control. [11] No clinical benefit was observed across the 80 included studies, across a spectrum of analgesic modalities. One included trial, however, found a significant reduction in pain at 6-months post radical prostatectomy with pre-emptive epidural analgesia. [12] An update on this systematic review revealed 30 further randomised trials published in the period 2001-2004. [13] Six out of eight trials published in this period reported reduced analgesic consumption and post-operative pain with pre-emptive NSAIDs .The results from studies evaluating other modalities remained uniformly negative.

A meta-analysis by Ong et al. [1] however supports the use of epidural analgesia, local anaesthetic wound infiltration and NSAID administration in the pre-emptive context. This analysis included RCTs comparing preoperative and intraoperative interventions. Outcomes measured were pain intensity scores, supplemental analgesic consumption and time to first analgesic consumption.

The meta-analysis by Ong et al. included 66 studies, with data from 3261 patients. The most marked effect size when combining outcome measures was observed with pre-emptive epidural analgesia (effect size 0.38; 95% CI, 0.28-0.47; p<0.01). Epidural analgesia produced a positive effect when the three outcome measures were considered individually.

For each of these outcome measures, an effect size was calculated in order to control for the variety of pain scales used across studies. The calculated effect size for each outcome was then combined to measure a single theoretical construct – termed ‘pain experience’. Where the effect size and confidence interval (CI) exceeded 0, the effect was deemed to be statistically significant. This differed to the approach by Moiniche et al., where the scores from the differing pain scales were converted into a single visual analogue scale (VAS) score and combined, and may have contributed to the conflicting results between the studies.

Anaesthetic wound infiltration and NSAID administration also produced statistically significant differences in ‘pain experience’. When outcomes were considered individually, time to first analgesic request was increased and analgesic consumption was decreased, but no effect on post-operative pain scores was observed. A 2012 systematic review of pre-emptive ketorolac administration observed decreased post-operative opioid requirements, and noted one small study which demonstrated benefits in post-operative pain scores. [14]

This meta-analysis includes trials that have since been withdrawn from publication. These trials related to pre-emptive local anaesthetic wound infiltration and NSAID administration. A re-analysis of the data by Marret et al. concluded that the retraction of these trials did not significantly alter the results of the study. [15] The study has further been criticised for a lack of detail regarding the review process, and the exclusion of non-English trials leading to publication bias. [1]

Katz and McCartney performed a systematic review of RCTs evaluating both pre-emptive and preventive approaches to analgesia, published from April 2001 to April 2002. [6] Of the twelve pre-emptive studies identified, five demonstrated a positive effect. The scope of the review is limited by the short time period analysed, but is the first to evaluate both pre-emptive and preventive study designs.

 Clinical evidence – preventive analgesia

15 studies evaluating the efficacy of preventive analgesia were identified by Katz and McCartney, nine of which were positive trials. [6] One of these positive trials, demonstrating pain reduction with bone marrow injection of opioids, has since been withdrawn from publication due to academic fraud. [16] Four of six studies examining the use of NMDA antagonists revealed lower post-operative pain and decreased analgesic consumption in the intervention group. Preventive effects were also observed with the use of clonidine and local anaesthetics.

The authors suggest that the percentage of positive trials observed in the study underestimates the true efficacy of preventive analgesia. This is because two of the pre-emptive trials may have in fact demonstrated preventive analgesia, but there was insufficient data presented regarding duration of analgesic effect to determine whether or not this had occurred. Three of the negative preventive studies were criticised due to inadequate provision of analgesia, thus precluding any preventive analgesic effect from occurring.

The limited amount of studies included means that the conclusions regarding the efficacy of preventive analgesia drawn from the review are weakened significantly by the retraction of the positive study by Reuben et al. [17] However, the study was influential in producing a shift from a pre-emptive approach to a preventive approach, by directly comparing these approaches in a single review. The efficacy observed in trials evaluating the role of NMDA antagonists also renewed interest in the role of these agents.

McCartney, Sinha and Katz performed a systemic review of RCTs evaluating NMDA antagonists (ketamine, dextromethorphan or magnesium) in preventive analgesia. [7] The primary outcome was reduction in pain, analgesic consumption or both in a time period beyond five half-lives of the drug utilised. Ketamine was found to have a positive effect in 58% (14 of 24) of included studies, and dexomethorphan was positive in 67% (8 of 12). No preventive effects were observed in four studies of magnesium.

The effect of NMDA antagonists on the incidence of CPSP is unclear. Low-dose intravenous ketamine administered with thoracic epidural analgesia has been observed to confer reduced post-thoracotomy pain in the immediate post-operative period and at one and three months after surgery. [18] A more recent RCT, however, noted no difference between ketamine and normal saline at four months post-thoracotomy, although it did confer post-operative pain relief. [19] The conflicting results may have been influenced by the difference in post-operative pain management, with the positive study providing a continuous ketamine infusion 3 days post-operatively. In the setting of colonic resection, a study of multimodal intraoperative epidural analgesia (local anaesthetic, opioids, ketamine and clonidine) revealed a reduction in pain 1-year post operatively. [20]

Practice guidelines

The aforementioned areas of uncertainty and controversy regarding pre-emptive and preventive analgesia have hindered the development of any formal guidelines to guide clinical practice. The Australian and New Zealand College of Anaesthetists (ANZCA) position statement ‘Guidelines on Acute Pain Management’ states that “preventive treatment of postoperative pain may reduce the incidence of chronic pain”. [21, p1] The ANCZA publication ‘Acute Pain Management: Scientific Evidence’ presents several key messages, and outlines the efficacy of pre-emptive epidural analgesia, preventive NMDA antagonist administration and ketamine (in colonic surgery only), but does not provide specific clinical recommendations. [9]

Regardless of the controversies that surround the issue, effective post-operative and long-term pain management is fundamental to quality patient care. Post-operative pain control should be individualised and a management plan should be developed prior to surgery, in partnership with the patient, taking into account psychosocial factors that may influence the pain experience. This should be based upon a thorough history, taking into account prior pain experiences, past analgesic use, current medications and immediate patient concerns. [2] ANZCA recommends a multimodal approach, as to improve efficacy of each drug, provide lower doses of individual drugs and reduce the risk of significant side effects. [21] Non-pharmacologic therapies should be instituted as a part of a multimodal approach where appropriate.

 

Conclusion

The process of central sensitisation has been the target of multiple methods of intervention in a wide array of treatment modalities, with the aim of decreasing post-operative pain, decreasing analgesic consumption and reducing the incidence of CPSP. The development of a meaningful evidence base has been encumbered by definitional confusion, difficulties with study design and academic misconduct leading to the retraction of articles. It is, however, apparent that the concept of pre-emptive analgesia should be replaced with the broader approach of preventive analgesia, and appropriate analgesia should be provided as long as a sensitising stimulus is present. Further research should focus on determining the analgesic regimens that most effectively decrease the clinical consequences of central sensitisation, including hyperalgesia, allodynia and CPSP.

Acknowledgements

The author would like to thank Dr. Andrew Powell, Staff Specialist Anaesthetist at John Hunter Hospital for providing feedback during the drafting of this article.

Conflict of interest

None declared.

Correspondence

L Anderson: luke.anderson2@hnehealth.nsw.gov.au

References

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[2] Vadivelu N, Mitra S, Schermer E, Kodumudi V, Kaye AD, Urman RD. Preventive analgesia for postoperative pain control: a broader concept. Local Reg Anesth 2014;7:17-22.

[3] Katz J, Clarke H, Seltzer Z. Review article: Preventive analgesia: quo vadimus? Anesth Analg 2011;113(5):1242-53.

[4] Dahl JB, Kehlet H. Preventive analgesia. Curr Opin Anaesthesiol 2011;24(3):331-8.

[5] Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006;19(5):551-5.

[6] Katz J, McCartney CJ. Current status of preemptive analgesia. Curr Opin Anaesthesiol 2002;15(4):435-41.

[7] McCartney CJ, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98(5):1385-400.

[8] Wall PD. The prevention of postoperative pain. Pain. 1988;33(3):289-90.

[9] Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM, editors. Acute Pain Management: Scientific Evidence. 3rd ed: Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine; 2010.

[10] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 Suppl):S2-15.

[11] Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology. 2002;96(3):725-41.

[12] Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally SE, Noble VE, et al. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. JAMA. 1998;279(14):1076-82.

[13] Dahl JB, Moiniche S. Pre-emptive analgesia. Br Med Bull 2004;71:13-27.

[14] De Oliveira GS, Jr., Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg 2012;114(2):424-33.

[15] Marret E, Elia N, Dahl JB, McQuay HJ, Moiniche S, Moore RA, et al. Susceptibility to fraud in systematic reviews: lessons from the Reuben case. Anesthesiology. 2009;111(6):1279-89.

[16] Ni-Chonghaile M, Higgins BD, Costello J, Laffey JG. Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia (Correction). Anesthesiology. 2009;110(3):689.

[17] Reuben SS, Vieira P, Faruqi S, Verghis A, Kilaru PA, Maciolek H. Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology. 2001;95(2):390-4.

[18] Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006;105(1):111-9.

[19] Duale C, Sibaud F, Guastella V, Vallet L, Gimbert YA, Taheri H, et al. Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain. 2009;13(5):497-505.

[20] Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005;103(4):813-20.

[21] Australian and New Zealand College of Anaesthetists Faculty of Pain Medicine. Guidelines on Acute Pain Management. ANZCA; 2013. [cited 2014 13/10]; Available from: http://www.anzca.edu.au/resources/professional-documents/pdfs/ps41-2013-guidelines-on-acute-pain-management.pdf.

Apoptosis is considered the main form of cell death in cancer cells undergoing cytotoxic treatments such as chemotherapy and radiotherapy. However, disappointing treatment response rates in some cancers have prompted a rethink regarding oncological control methods. Cellular senescence has emerged as a possible tumour suppression strategy that may effectively control cancer cells when apoptosis fails. Understanding the mechanistic workings of senescence in the context of cancer cells may shed light on its feasibility as a clinical strategy.

Introduction

Conventional cancer therapeutics such as chemotherapy rely heavily on cytotoxicity to achieve maximal cell death. The rationale behind this approach is that elimination of cancer cells, and consequently tumour burden, will help achieve the best clinical outcome. Induction of cell death as an immediate clinical endpoint might be seen as an obvious choice, but it is worth contemplating whether this short-term benefit is incurred at the expense of long-lasting remissions. Many of the anti-cancer agents used in chemotherapy activate DNA damage signaling pathways which lead to apoptosis. However, apoptotic pathways tend to be defective in cancer cells. This could explain why response rates are sub-optimal despite aggressive regimens. The continued use of cytotoxic agents also promotes the development of resistant clones which can repopulate the primary tumour or metastasise to distal sites. If cell death is not always the best way to achieve sustainable cancer control, is there an alternative strategy or endpoint that overcomes the subversion of apoptotic cell death by tumour cells and is just as effective in blunting their proliferative nature?

One possible answer seems to be the induction of cellular senescence. Cellular senescence is classically defined as an irreversible state of growth arrest that occurs when cells encounter stress stimuli. Senescent cells are characterised by the following major features (Table 1).

 

Different forms of cellular senescence such as replicative (i.e. due to telomere shortening) or oncogene-induced senescence exist. Senescence-like phenotypes can be rapidly induced by genotoxic stress imposed by chemotherapy or radiotherapy, also known as accelerated cellular senescence (ACS). [1] Both apoptosis-competent and apoptosis-defective cancer cells may still be controlled by senescence, therefore implicating it as an important tumour-suppressive mechanism. [2] However, chemotherapy may not always provide durable responses as subsets of cancer cells are capable of escaping senescence and resuming cell division. The utility of senescence has, thus, remained inconclusive. This article will attempt to briefly explore the mechanistic insights of cellular senescence in cancer cells and assess its feasibility as a clinical strategy or endpoint in oncological control.

Mechanistic insights into the role of cellular senescence in cancer cells

It was originally observed that cells that undergo senescence often do not divide even in the presence of mitogenic stimuli. Genomic stress from the environment can induce DNA damage pathways which inhibit cell cycle progression. In cancer cells, two important pathways are the p53 and p16INK4a/pRB pathways. [2] p53, p16INK4a, and pRB are important tumour suppressor proteins. While the mechanisms are still unclear and the contributions of p53 and p16INK4a may differ in different cancer cell types, it is suggested that p53 may be important for the establishment of senescence while p16INK4a maintains it (Figure 1). [3,4]

 

Activation of p53 by stresses such as oxidation and telomere dysfunction lead to upregulation of the cyclin-dependent kinase (CDK) inhibitor p21^Waf1 which, in addition to apoptosis, causes cell cycle arrest and senescence. The activity of p53 is sustained by stress-induced DNA damage response signals which come from DNA damage foci, also known as DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). On the other hand, p16INK4a is essential for maintenance of senescence via the activation of the retinoblastoma (pRB) tumour suppressor protein. The pRB protein helps form senescence-associated heterochromatin foci (SAHF) which can silence tumour-promoting genes. [4]

Cancer cells can be cleared by apoptotic cell death, however, those which are resistant to initial apoptosis may be diverted to alternate pathways such as senescence, where they face a number of possible outcomes. [5] Firstly, cancer cells that undergo senescence are still capable of being eliminated by apoptosis at a later time. Secondly, senescent cancer cells may go into a terminal proliferative arrest state. It has been suggested that there is significant cross-talk between terminally arrested cancer cells and the immune system. Prolonged terminal arrest can trigger the clearance of cancer cells via phagocytosis and immunogenic cell death by autophagy. [6] Alternatively, immune mediators such as cytokines may be required for the maintenance of terminal arrest. [7] Dysregulation of this cross-talk can potentially result in bypass of cellular senescence and escape of cancer cells. The second outcome is interesting in a therapeutic sense as the involvement of immunogenic cell death is likely to bring about more sustained control than apoptosis. Apoptosis generally does not trigger an inflammatory response and the fact that cancer cells may harbor apoptotic defects suggests that this method of tumour suppression is not efficient. In fact, there is recent evidence that apoptosis may not even be the predominant mode of cell death in most cells, implying that other modes of cell death should be considered in cancer therapy. [8]

Senescence-associated secretory phenotype

While senescent cells exist in a state of growth arrest, they are still metabolically active and secrete a number of cytokines, chemokines, growth factors, and proteases which have important tumour-suppressive and tumour-promoting consequences. This unique phenotype is known as senescence-associated secretory phenotype (SASP) and can be found in senescent cells with DNA-SCARS. [9] As mentioned above, terminal arrest may be maintained by certain immune mediators. [4] These immune mediators may be secreted in an autocrine manner and help reinforce growth arrest. Examples of these tumour-suppressive mediators include plasminogen activator inhibitor-1 (PAI-1), and insulin-like growth factor binding protein-7 (IGFBP-7). On the other hand, tumour-promoting mediators can be secreted in a paracrine manner and induce aggressive phenotypes in neighbouring cells. These include factors such as matrix metalloproteinases (MMPs), amphiregulin, vascular endothelial growth factor (VEGF), as well as growth-related oncogene-alpha and beta (GRO-α & GRO-β). [4]

Certain pro-inflammatory cytokines such as interleukin-6 and interleukin-8 (IL-6 and IL-8) have paradoxical effects on tumour progression and their exact role may depend on the immune contexture. Chronic low-level inflammation can promote tumour progression whereas an acute high-grade inflammatory response can result in tumour regression. [10] It is worth postulating that the stimulation of immunogenic cell death via the second outcome may actually assist in augmenting pro-inflammatory cytokine levels in the acute phase, leading to elimination of cancer cells. On the other hand, apoptosis does not promote adequate IL-6 and IL-8 levels to result in clearance of these cells. Instead, epithelial-to-mesenchymal transition and the cell migration/invasion effects of these cytokines may become dominant, resulting in metastatic phenotypes. Besides secreting chemokines to attract immune cells, senescent cells also express ligands for cytotoxic immune cells such as natural killer (NK) cells, allowing for immune-mediated clearance of cancer cells. [11] It would seem counterintuitive that cellular senescence can have tumour-suppressive and tumour-promoting effects at the same time. How then, can we reconcile these paradoxical effects?

A temporal model of senescence

Cellular senescence is not a phenomenon restricted to cancer cells. In fact, it is a highly conserved process also found in normal cell types such as fibroblasts, and is involved in tissue repair as well as age-related degeneration. [12] Many of the tumour-promoting secreted factors found in the SASP are actually required for tissue regeneration. For example, VEGF is involved in angiogenesis while MMPs are required for degrading of fibrotic tissues found in damaged tissues. [13] Similarly, ageing tissues are characterised by low levels of chronic inflammation which can be mediated by factors such as IL-6 and IL-8. [14] The SASP is therefore a changing entity which differs in its secretory repertoire depending on the context it is expressed in. Rodier and Campisi proposed a model in which the senescent phenotype can be organised temporally. [15] In this model, the senescent phenotype increases in complexity with time. The initiating event is an oncogenic stress which either results in immediate repair and recovery of cells or induction of senescence.  Once senescence occurs, cells are terminally arrested, resulting in tumour suppression. The SASP is then activated and IL-1α is secreted. This cytokine binds to the IL-1 receptor and induces a signalling cascade which leads to the activation of transcription factors such as NF-kB and C/EBPβ. This in turn simulates SASP factors such as IL-6, IL-8, and matrix metalloproteinases (MMPs) which are involved in both tissue repair and tumour progression. At the same time, pro-inflammatory cytokines such as IL-6 and IL-8 may increase to such high levels that they feed back and reinforce tumour suppression.

In addition, senescent cells may express a number of cell surface ligands and adhesion molecules which attract immune cells and result in clearance. During the later stages of senescence, the SASP phenotype is tuned down through the expression of microRNAs such as mir146a and mir146b so as to prevent the persistence of an acute inflammatory response. [16] However, the consequence is a chronic inflammatory state which can be perpetuated by imperfect immune clearance. A small number of senescent cells persist and contribute to chronic inflammation via their pro-inflammatory cytokines, which can eventually lead to the formation of an ageing phenotype. This phenotype is characterised by impaired functionality and increased vulnerability to cell death. It is apparent from this model that there is a delicate balance between different SASP phenotypes and imperfect immune processes can easily tilt the balance towards detrimental outcomes such as tumour progression and ageing phenotypes.

Susceptibility to tumour progression is not unexpected considering that important tumour suppressive proteins such as p53 and p16INK4a are often deficient or defective in cancer cells. [17] Although the defects in p53 and/or p16INK4a can be hurdles, these ‘weaknesses’ also provide unique opportunities for therapeutic interventions. In fact, cellular senescence might have originated foremost as a beneficial biological response. From an evolutionary perspective, it is suggested that senescence could have evolved to promote tumour suppression and tissue repair in young organisms. [4] These activities were selected as they are necessary for organismal survival in early harsh environments. However, unselected activities such as tumour progression and aging still occur as survival to old age is rare in harsh environments, and therefore selection against these detrimental activities is weak and tends to decline with age. It is therefore quite likely that senescence was meant to be a major tumour-suppressive mechanism and not simply a ‘backup’ plan to the more widely recognised apoptotic cell death.

Cellular senescence as a clinical strategy

While cellular senescence was initially thought to be irreversible in normal cells, a few studies have suggested that this process is reversible in cancer cells under the right conditions. For example, studies focusing on the tumour suppressors p53, pRB, and p16 found that suppression of these proteins in fibroblasts led to the reversal of the senescent phenotype. [18] Similarly, lung cancer cells were able to escape senescence through the up-regulation of Cdc2/Cdk1 and subsequently increased production of survivin, a protein involved in cell resistance to chemotherapy drugs such as paclitaxel. [19] This potentially implicates senescent cells as a repository for re-emergence of carcinogenesis. However, it should be noted that that there is a lack of evidence which suggests that cell-cycle re-entry is a sign of recovery of full proliferative capacity. Cells which re-enter the cell cycle may still be subjected to cell death by apoptosis or mitotic catastrophe at a later stage. [20]

In solid tumours, the use of chemotherapy alone yields a disease response rate of 20-40% and complete tumour eradication is often difficult to achieve. Considering that most anti-cancer agents kill by apoptotic cell death, this seems to suggest that apoptosis may be limited in its clinical efficacy. [21] Furthermore, regardless of whether cellular senescence is reversible or not, in vivo analysis of treatment responses in primary lymphomas have shown that senescence improves the outcome of cancer therapy despite the lack of intact apoptotic machinery. [17] One of many possible reasons for the improved outcome could be the prevention of cancer stem cells (i.e. precursor cancer cells) via the inhibition of mechanisms similar to induced pluripotent stem (iPS) cell (i.e. stem cells generated from adult tissue) reprogramming. [21] This is because potent inducers of senescence such as p53 and p16INK4a are also potent inhibitors of iPS reprogramming. There is also potential for senescence-based therapies to yield synergistic and additive treatment effects as conventional modalities such as chemotherapy and radiotherapy can induce ACS. [22] Therefore, attempts should be made to further consider senescence as a potential treatment strategy.

There are a number of possible directions that can be pursued in a senescence-based strategy. Firstly, the activity of tumour suppressor proteins and senescence-inducers such as p53 can be enhanced. This can be attained through p53 stabilisation or mutant p53 reactivation. p53 stabilisation was found to be mediated by small molecules known as nutlins. These molecules inhibit the E3 ubiquitin-protein ligase MDM2, which is a potent inhibitor of p53. Similarly, restoration of p53 was achieved by compounds such as the pro-apoptotic factor PRIMA-1^MET  and DNA intercalator ellipticine, which  induce structural changes in the mutant protein and promote transcription of p53 targets . [23,24] Another possible target could be the inhibition of cell cycle progression via CDK inhibitors. One of the first CDK inhibitors to be tested in clinical trials is flavopiridol, which has been shown to exert tumour-suppressive effects in a number of malignancies such as colon and prostate cancer. [25] Flavopiridol, in certain doses, also appears to enhance treatment response when used in conjunction with standard chemotherapy agents, illustrating the proof of concept that senescence can augment existing treatment modalities.  More recently, studies have investigated the use of statins in patients after neoadjuvant chemotherapy. Statins were shown to down-regulate key cell cycle mediators such as Cdk1, cyclin B1, and survivin, and up-regulate the CDK inhibitor p27. [21] However, antagonistic effects were also observed when statins were administered alongside chemotherapy due to escape from senescence. These observations suggest that the effects of statins need to be examined further, particularly in relation to their use before, during, or after chemotherapy. Besides modulation of p53 function and the use of CDK inhibitors, senescence can also be induced by inhibition of important oncogenes such as MYC. [26] MYC over-expression in tumours is associated with a poor prognosis when chemotherapy is used. By inhibiting MYC through small molecule inhibitors such as 10058-F5 and its derivatives, the expression of a number of genes involved in cell proliferation can be suppressed, contributing to cellular senescence. [27]

Conclusion

In summary, cellular senescence may be a viable strategy for oncological control. Although its therapeutic potential was first recognised through its ability to bring about permanent growth arrest of cancer cells, this viewpoint is too simplistic. Cellular senescence is in fact a dynamic process characterised by a SASP which evolves in complexity with time. The reversibility or irreversibility of cellular senescence depends on the immune context and delicate processes that regulate senescence (e.g. immune clearance and deficiency of tumour suppressive proteins). Although senescence is dependent on multiple factors, we should consider it as a major tumour-suppressive mechanism alongside apoptosis. During carcinogenesis, subversion of anti-tumour responses is commonplace and should not be perceived simply as weaknesses in a clinical strategy. This is illustrated by the observation that cancer cells that do not apoptose can still subsequently undergo apoptosis at a later stage or are subjected to more immunogenic forms of cell death like autophagy. Senescence can therefore function as a potent failsafe tumour-suppressive mechanism.  On the contrary, therapeutic interventions should anticipate and augment existing barriers to tumour progression. In senescence, a number of possible solutions such as p53 enhancement, CDK inhibitors and oncogene inhibition provide reason for optimism and should be investigated further.

Acknowledgements

None.

Conflict of interest

None declared.

Correspondence

K Ho: koho2292@uni.sydney.edu.au

References

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[3] Yan Q, Wajapeyee N. Exploiting cellular senescence to treat cancer and circumvent drug resistance. Cancer Biol Ther 2010; 9(3):166-75.

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[5] Chitikova ZV, Gordeev SA, Bykova TV, Zubova SG, Pospelov VA, Pospelova TV. Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers. Cell Cycle 2014; 13(9):1424-39.

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Substance use disorder has been a significant issue within the medical profession throughout history. It is recognised as an important issue of concern, particularly due to its associated mortality, morbidity and social consequences. Although a substantial body of literature addresses this issue amongst doctors, there is little discussion focusing on medical students. This review summarises the existing literature available on the epidemiology, common  presenting  features,  management,  legal  implications and mandatory notification requirements of substance abuse in the medical student. Limited evidence suggests concerning levels of hazardous alcohol use exists in medical students, however alcohol and drug use is not comparatively higher than the general student population. While early detection is optimal for harm prevention, signs and symptoms of substance abuse are subtle and easily missed. Prevention and early intervention is critical, and it is important for students to recognise possible signs of substance abuse  in  their  colleagues,  as  the  biggest  barrier  to  treatment is   denial.   Once   detected,   current   evidence   from   Physician Health Programs suggests a service to manage the student’s multidisciplinary  care,  follow  up  and  return  to  study  obtains the best outcome. As a chronic medical condition that carries significant risk of harm to the impaired student – and potentially to patients – all health professionals should be aware of this issue and their mandatory reporting obligations.

Introduction

Substance use disorder (SUD) amongst doctors is an issue of significant concern. It is estimated the lifetime prevalence of substance abuse in Australian doctors is approximately 8%. [1] There is limited literature or discussion, however, addressing this issue in the context of the most junior members of the profession, medical students. The university experience is often coupled with alcohol use and occasionally with casual illicit drug use, but this is, to some extent, accepted, perhaps as part of youthful exuberance, experimentation or a rite of passage. [2] For some, however, this substance use may manifest as, or progress to, substance abuse: a pattern of drug or alcohol use that is detrimental both to the individual and to society. [3] For the substance-abusing medical student, there is a wide scope for serious implications personally, professionally and with the public.

This article aims to highlight the importance of this topic and provide information  on  the  concept  of  substance  use  disorder,  common signs  of  substance  abuse,  management,  reporting  requirements and legal implications. It also addresses why it is imperative there is awareness for this issue in medical students to prevent serious health consequences and risk to the public.

Terms within this article

Substance use disorder or substance abuse: A chronic condition characterised by a pathological pattern of behaviours related to substance use, manifesting as two or more symptoms of: impaired control of drug use; social impairment at work, school or home; risky use; tolerance or withdrawal. [4]

Substance   dependence:   An   inability   to   control   substance   use, despite problems caused by use. [5] This may manifest physically or psychologically with tolerance or withdrawal. Dependence and drug abuse are not separate entities within the Diagnostic and Statistical Manual 5 (DSM-5), however these terms are prevalent in the cited literature.

Impairment: A physical or mental impairment, disability, condition or disorder (including substance abuse or dependence) that detrimentally affects, or is likely to detrimentally affect, a practitioner’s capacity to practise the profession. [6]

How common is student substance abuse?

There  is  little  recent,  comprehensive  data  on  student  substance abuse, with most studies occurring in the 1980s-1990s and concerning rates of use rather than abuse. [5] Furthermore, prevalence studies are hindered by surveys requiring self-reporting of abuse and varied case definitions. With these limitations, the available data on student substance use is summarised below.

Alcohol use and abuse

Use of alcohol in the general student population is common, with consumption occurring in approximately 96% of Australians aged 18-21 years. For medical students in particular, international studies have indicated that rates of lifetime alcohol usage range between 62.3% and 98.1%. [2,5,7-11] Male medical students have higher levels of intake compared to females and hazardous alcohol use is significantly higher in those with high levels of psychological distress. [12] The BeyondBlue study of medical students and doctors found concerning rates of moderate-risk (21%) and high-risk (4%) drinking amongst medical students in Australia. [12] Moderate risk is classed as a hazardous intake level and high risk is associated with harmful drinking patterns, as assessed by the World Health Organisation Alcohol Use Disorders Identification Test (AUDIT). [12] This level of drinking, however, appears low in comparison to the general university population, which has an approximately 8.1% rate of harmful drinking. [12,13]

Internationally, 50% of medical students in the UK consumed above the recommended amount. [8] Using the CAGE questionnaire (Table 1),  22.4%  of  junior  Turkish  medical  students  and  52.5%  of  Irish medical students were found to be CAGE positive. [10,11] Of medical students who drink, 60.5% of men and 72.2% of women engaged in binge drinking, with 36.8% of men and 58.2% of women suggesting that their performance had been affected at least one day in the past month by alcohol consumption. [8] While the BeyondBlue study noted that drinking levels decreased with age, other data suggests that as students progress through their clinical years and beyond, a greater number of students drink, and drink more heavily. [10,14]

Drug use

Rates of illicit substance abuse in medical students appear comparable to, or less than that of, the general population, with data falling between 3-10%. [17] BeyondBlue reports show low rates, with 10.2% of students engaged in illicit drug use 2-3 times a month, and 0.5% 1-6 times a week. [12]

Drugs of abuse may be recreational, for example cannabis or stimulants, or prescription, such as benzodiazepines, opiates or propofol. Amongst junior students, the most common drug of abuse is cannabis and is often likely to be the first used before medical school. [2,8,14] Other illicit or prescription drugs are less common, however alcohol and cannabis might be considered gateway drugs to these. In one study, those who used cannabis were more likely to be drinking heavily than non-users and those who used illicit drugs had also used cannabis. [14] It is reported that medical students are increasingly being offered illicit drugs, and more are accepting them. [11] Abuse of illicit drugs, such as cocaine, or prescription drugs, such as benzodiazepines, was more likely to occur once at university. [2]

Notably, as students progress to become doctors, patterns of drug abuse change with increasing rates of prescription drug abuse. [5,10] Drugs of choice vary by medical specialty as to what is easiest to obtain; for example, anaesthetists have high rates of propofol and opiate abuse, whereas other specialties such as psychiatrists are more likely to abuse benzodiazepines. [1,18,19].

Recognition of substance abuse

Signs  of  substance  abuse  are  both  subtle  and  varied,  and  can  be easily missed. They are often disguised by the affected practitioner. Denial is common, and often it is the person with the disorder that is last to acknowledge a problem. [20] Early detection can prevent the development of significant harm. Table 2 lists possible emotional, social and physical signs of alcohol or drug abuse.

Reporting requirements

The impaired physician is a concept defined under national law as a physical or mental impairment, disability, condition or disorder (including substance abuse or dependence) that detrimentally affects, or is likely to detrimentally affect, a practitioner’s capacity to practise the profession. [6] For a student, the impairment must detrimentally affect, or be likely to detrimentally affect, the student’s capacity to undertake clinical training. This means impairment is defined by a student’s reduced capacity to learn, a quite broad definition. For a notification to the Australian Health Practitioner Regulation Agency (AHPRA) to be made, however, there must be a belief that their impairment could cause public harm, for instance intoxication at work. [6,23]

Two forms of notification can be made to AHPRA. [6] Mandatory notifications compel  practitioners  or  education  providers  to  make a notification if they form a reasonable belief that a student has an impairment that may place the public at substantial risk of harm in the course of their clinical training, or are practising whilst intoxicated with alcohol or drugs. Voluntary notifications about a student can be made by anyone if they form a reasonable belief that a student has an impairment that may cause public harm.

Consequences  of  notification  may  include  the  suspension  of  a student’s registration, the imposition of conditions of practice, further health assessment, and possible long-term impacts on their ability to continue their studies and future registration (depending on expert advice in each case). [6,23] For students, it is important to recognise the possible future career consequences of alcohol or drug abuse.

Management of the impaired student

Treatment  of  impairment  is  both  complex  and  individualised  and there is no standard protocol for treating impaired medical students. Treatment may be managed by the student and their treating team, or may be arranged by AHPRA or the medical board as a result of a notification.  Individual  medical  school  impairment  policies  likely vary and are not reviewed here. A majority of reviewed American school policies require direct referrals for management of suspected substance abuse cases, and one third forego disciplinary treatment for those impaired students who self-refer to promote seeking early intervention. [5] Depending on the substance(s) involved, treatment may include features such as inpatient treatment and detoxification, 12 step programs or use of therapeutic agents (e.g. naltrexone). [3]

Referral to a long-term support program with a specific focus on doctors’ health is optimal. Within Australia, available services and models of support vary from state to state. Most states offer a Doctor’s Health Advisory Service telephone counselling service, with support offered by experienced practitioners. [24] The Victorian Doctors’ Health Program (VDHP) offers the only full-time physician health program (PHP) of its kind in Australia. It is confidential, independent of AHPRA and open to both doctors and medical students. [25] PHPs were pioneered in the United States to assist in the rehabilitation of impaired physicians. They do not directly provide treatment but provide evaluation and diagnosis, facilitation of formal addiction treatment, on-going confidential support, case management, biochemical and workplace monitoring,  and  return-to-work support  as  required  on a case-by-case basis. [25,26] A core component is an individualised care contract lasting up to five years to ensure compliance with the appropriate treatment plan devised. This may include a case manager, psychiatrist, addiction specialist, psychologist, general practitioner or social worker. Ongoing peer support is also recommended through a facilitated Caduceus collegial support group open to medical practitioners and students with substance abuse issues, and has been shown to play an important role in recovery. [1] The VDHP offers three types of programs of different levels of support, ranging from intensive case management to wellbeing and support programs and long term follow up, depending on what is required in each case and the phase of recovery. These programs are successful, with studies consistently demonstrating success rates of 75-90% after five years for American physicians treated through PHPs. [27,28] Preliminary data from the VDHP program indicates similar Australian five-year success rates. [25]

The evidence-based success of these programs suggests that similar services should be available for all doctors. However, cost is a significant issue. The average American state PHP costs USD$521,000 annually to manage between 65 to 75 physicians per year, primarily paid for by an additional $23 charge to licensing fees, whilst formal treatment costs are covered by health insurance and personal physician contributions. [27] It is important to note that some PHPs produce better outcomes than others and that implementation should replicate published successful models and be followed with outcome evaluations. [29,30]

Further to specific services available to doctors, there is a wealth of support available through the pastoral support and wellbeing services of universities that can be accessed in a student capacity. One proactive university  even developed and successfully implemented an Aid for the Impaired Medical Student program to oversee medical student recovery management, although little has been published on this recently. [31]

Fighting the “conspiracy of silence”

Boisaubin and Levine discuss the concept of a “conspiracy of silence” where the impaired physician, his/her colleagues, friends and family have a tendency to dismiss their suspicions and suppress their concerns, with a belief that the physician is fine, or capable of solving his/her issues. [32] They state “denial is the most consistent hallmark of this disease process, for both colleagues and the susceptible physician.” This is a key barrier to treatment, and only increases with professional advancement in a medical culture of not admitting weakness, let alone acknowledging the presence of a medical condition laden with stigma. Participants in the VDHP substance use programs were most likely to have been referred by colleagues, employers or treating doctors, compared to self-referral or referral from regulatory bodies. [1] This demonstrates the importance of students and educators being aware of the signs of substance abuse in others, and knowing the options available to assist.

Future implications

There is little data about the risks of student substance abuse, but death or near fatal overdose is the presenting symptom in 7-18% of doctors. [33] Alarmingly, recent data demonstrates anaesthetists abusing propofol have a 45% mortality rate. [19] Substance abuse is also often coupled with psychiatric morbidity and stress-related disorders. Harm to patients is a real risk, either indirectly through impairment of capacity and decision making, or directly, such as in the well-publicised case of the fentanyl-abusing doctor spreading Hepatitis C to women undergoing pregnancy terminations. [34]

There is no clear longitudinal data to demonstrate whether substance abuse as a student is associated with substance abuse as a doctor. This article does not enter the debate as to whether impairment due to substance abuse as a student should preclude a student pursuing a career intimately associated with a range of drugs of abuse, such as opiates. Without prescribing rights, students are more limited in their access to the wide range of substances, compared with their qualified colleagues. It was noted that, of those surveyed in an evaluation of the VDHP Caduceus program, substance abuse issues began in medical school for 16% of the respondents. [1] Furthermore, the diagnosis of alcohol abuse is commonly delayed, often for years, and can start with patterns of high risk drinking.

Conclusion

In conclusion, substance use disorder has enormous impacts, including health  issues,  patient  risk,  mandatory  notification  requirements, future career implications and ultimately escalation to more dangerous substances. It is a chronic medical condition and management requires a multidisciplinary team, long-term support, sensitivity and experience. It is important to recognise that, while medical students are often high functioning and high achieving and generally appear to have similar rates of substance use to the general university population, they are not immune to substance abuse issues. In a profession with high levels of psychological distress, burnout and minor psychiatric morbidity, it is necessary to have a higher index of suspicion. [12] The biggest barrier to treatment is denial, not only by the impaired student, but also by friends, family and colleagues. It would therefore seem imperative that student substance abuse is detected early and treatment provided immediately to prevent the serious consequences of ignoring the situation.

If this article raises concerns for you or anyone you know, information on your local state service can be accessed at the Australasian Doctors’ Health Network website http://www.adhn.org.au/. Crisis support is available 24hrs/day from Lifeline Australia on 13 11 14.

For useful general wellbeing information focused on medical students, Keeping Your Grass Greener is a fantastic guide available from the Australian Medical Student Association at: https://www.amsa.org.au/ initiatives/community-and-wellbeing/keeping-your-grass-greener/

Acknowledgements

The author wishes to acknowledge Dr Kym Jenkins, Clinical Director of the Victorian Doctor’s Health Program for information on the management of substance abuse in Australia.

Conflict of interest

None declared.

Correspondence

L Fry: lefry3@student.monash.edu

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