3.15 The impact of smoking on treatment of disease

Last updated: Jan 2021
Suggested citation: Just, J, Winnall, W, Hurley, S, Greenhalgh, EM & Winstanley, MH. 3.15 The impact of smoking on treatment of disease. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2021. Available from  http://www.tobaccoinaustralia.org.au/3-15-smoking-and-complications-in-medical-treatmen

 

3.15.1 Surgery

Smoking increases the risk of intraoperative (anaesthetic) and postoperative complications.1 Smokers’ higher prevalence of chronic diseases, impaired pulmonary reserve and altered immune responses are thought to contribute to these complications. Poorer surgical outcomes result.2

In 2020, the World Health Organization released an updated review of tobacco and post-surgical outcomes that suggested that smokers who quit around 4 weeks prior to surgery have a lower risk of operative complications. However, the ideal cessation time varies according to the specific complication.3

3.15.1.1 Anaesthesia

The effectiveness of a number of commonly used anaesthetic drugs is reduced in smokers. Higher doses are therefore required. These drugs include opioids,4 neuromuscular blocking agents and some of the volatile agents that are administered by inhalation (via a mask or endotracheal tube).5 The polycyclic aromatic hydrocarbons in cigarette smoke induce the liver enzymes that metabolise anaesthetics, at least partly accounting for these effects. Smoking does, however, decrease postoperative nausea and vomiting, possibly because of the increased metabolism of volatile anaesthetics.5

Smoking cessation before surgery can reduce the requirement for perioperative opioids, demonstrated in a study of people having laparoscopic distal gastrectomy with gastroduodenostomy (removal of part of the stomach). People who quit for longer than one month prior to surgery required less perioperative opioids than those who quit for less than one month prior to surgery.6

Smoking also increases the risk of intraoperative respiratory complications, including bronchospasm, aspiration, hypoventilation and hypoxaemia.7-9 A higher concentration of remifentanil may be needed to prevent cough during emergence from anaesthesia for smokers compared to non-smokers.10

The Australian and New Zealand College of Anaesthetists recommends that patients who smoke be encouraged to quit at any time before surgery.11  Research suggests that recent quitters are no worse off than continuing smokers in terms of pulmonary complications. (see Section 3.15.1.3).12, 13

3.15.1.2 Postoperative complications

It is well-established that smoking results in a significantly increased risk of many postoperative complications. These complications include a higher risk of general morbidity, wound complications, lung complications, infections, neurological complications and an increased risk of intensive care unit (ICU) admission post-surgery.14

-Wound and surgical site complications

Smoking delays wound healing after surgery.1 Complications for which smokers have a greater risk include: wound infection;15 dehiscence (bursting of sutures);16 erosions (destruction of tissue surfaces) and necrosis (death of most of the cells of a piece of tissue or an organ);17 hernia (protuberance of organs through cavity walls); poor healing of broken bones; poor healing of fistulae (abnormal openings from body organs to the surface of the skin) and incomplete wound healing in people with critical limb ischemia undergoing endovascular interventions.18-21  

Smoking has an impact on wound healing via several different pathophysiological mechanisms, including:22, 23

  • Reduced blood flow to, and oxygenation of, peripheral tissues
  • Impaired inflammatory processes that are part of normal healing
  • Impaired proliferation of fibroblasts and collagen production
  • Impaired immune function, which may increase the risk of wound infection3

Such wound complications are particularly problematic after plastic and reconstructive surgery, bariatric surgery, bowel surgery, hernia repair surgery, dental surgery (see Section 3.11.4), microsurgery, and organ transplantation.11, 17, 24-26

-Complications following cardiac surgery and cardiac procedures  

A meta-analysis found smokers undergoing cardiac surgery were at increased risk of pulmonary complications and pneumonia following surgery, but had a reduced risk of kidney complications, compared to ex-smokers.27

A systematic review and meta-analysis of patients undergoing repair of an aneurysm (enlargement or ballooning of an artery due to a weakness in the artery wall) found that smoking was protective again endovascular leaks post-surgery.28 The paper proposed possible explanations for this; smokers are more likely to have extensive atherosclerosis, potentially protecting against leakage, and smoking increases aggregation of platelets, increasing clot formation, so leakage becomes less likely.

Smokers had an almost two-fold increased chance of poor outcomes (death, myocardial infarction, or stroke) within five years after coronary revascularisation, whereas former smokers were not at increased risk.29 Smokers also have an increased risk of death after carotid endarterectomy (plaque removal procedure to reduce the risk of stroke).30

-Complications following orthopaedic surgery

Smokers have an increased risk of complications following several types of orthopaedic surgery (see Section 3.13.2), including shoulder surgery, and hip and knee arthroplasty (replacement).31-37 Smoking is an independent risk factor for complications after shoulder surgery (open rotator cuff repair), including 4.6-fold higher chance of a thromboembolic event (blood clotting, such as deep vein thrombosis), 6.4-fold higher chance of pulmonary embolism (blood clot in the lung),38 2.5-fold higher chance of return to the operating room, 1.6-fold higher chance of readmission and 4.7-fold higher chance of sepsis or septic shock.39

A meta-analysis found smokers had a higher risk of loosening of prostheses (artificial body parts inserted during surgery), deep infection, and the need for revision following total hip arthroplasty (hip replacement).31 Another study found an increased risk of periprosthetic joint infection (infection around the artificial body part) in smokers undergoing total hip or knee arthroplasty.33 A meta-analysis of 10 studies from 2020 found that smokers were at 1.5-fold increased risk of prosthetic joint infection requiring surgery after total hip replacement.40

People who smoke had almost four-fold greater odds than non-smokers of needing re-operation after a common spinal procedure called posterior cervical decompression,41 and a 2.5-fold increased chance after lumbar discectomy.42 Smoking was a risk factor for longer stay in intensive care after surgery for spine trauma.43 Smokers also had increased pain and disability one year after a spinal surgery called lumbar tubular microdecompression.44

After accounting for the effects of other risk factors, smoking was an independent risk factor for major complications after hand surgery. A large cohort study of over 48,000 people having hand surgery showed that smokers were at higher risk of infections and wound healing complications.45 Smokers have a higher risk of adverse events within 30 days of surgical treatment for a broken wrist. Smokers had a 1.75-fold higher risk of any adverse event, 1.73-fold higher risk of infection, 2.1-fold increased risk of reoperation and 1.8-fold increased risk of readmission compared to non-smokers.46 Smoking was also associated with a small increase in the chance of needing readmission for complications after craniotomy surgery47 and repair of small umbilical and epigastric hernias.48

A study also found smoking increases the risk of venous thromboembolism (VTE) (blood clots that form in veins) following anterior cruciate ligament (ACL) reconstruction surgery.49 Another study found smokers had higher rates of wound infection, VTE and subsequent ACL reconstruction compared to non-smokers.50

-Complications following plastic and reconstructive surgery

Following breast reconstruction, smoking has been associated with a doubling of the risk of complications (such as mastectomy flap necrosis and infection) and a five-fold increase in the risk of implant failure.51 Such poor surgical outcomes have led to a call for caution when undertaking breast reconstruction in smokers.52 Similarly, impaired wound healing and wound infection in smokers undergoing breast reduction surgery53, 54 have led to a suggestion that pre-operative smoking cessation be an essential eligibility criterion for this surgery.54 In another study of patients undergoing reduction mammaplasty (breast reduction), smoking was associated with an increased risk of wound complications including dehiscence.55, 56

-Complications following transplant surgery

Smokers undergoing organ transplantation have poorer outcomes,57 including increased mortality after liver transplantation,24 increased kidney transplant rejection,58 and poorer survival after heart transplantation if either the donor was, or the recipient is, a smoker.59-63

Unsurprisingly, solid organ transplant recipients who smoke post-transplant are at higher risk of newly diagnosed cardiovascular disease, cancer and overall shorter survival time, and  mortality.61

The poorer organ transplantation outcomes in smokers, combined with the high demand for donated organs, have led to suggestions that smokers be given lower priority for organ transplants and debate about the ethics of such a policy.64-66

Where the transplant donor was a smoker, there is also an increased risk of poor outcomes. People with a history of smoking who donated a kidney during live kidney donation have 3.3-fold higher chance of developing chronic kidney disease after the surgery.67 A donor history of smoking is associated with an increased risk of clotting after liver transplant, and increased risk of graft rejection and mortality in the recipient.68

 

-Complications following other types of surgery

Smoking increases the risk of complications following other types of surgery including: a higher failure rate for oral mucosa graft urethroplasty (repair of the urethra with a graft from the lining of the mouth);69 worse hearing and the need for repeat operations after ear surgery;70 increased complications post appendicectomy71 and hernia repair;26, 72 and increased risk of complications following bariatric surgery including prolonged intubation (insertion of a tube through the mouth to support artificial breathing) and organ space infection (a type of surgical site infection).73 Another study suggested that in patients undergoing sleeve gastrectomy (surgery involving removal of part of the stomach) for weight management, smokers had an increased risk of morbidity and mortality compared to non-smokers (of note, ‘smokers were those who had smoked at least one cigarette in the year prior to surgery, ‘non-smokers’ were those that had not).74 A systematic review of the association of smoking with post-operative complications after bariatric surgery found that smoking was an independent risk factor for increased 30-day mortality and major and pulmonary complications. Smoking was also associated with long-term complications such as ulceration and bone fracture but had minimal effect on weight loss following surgery.75

Smokers having a lobectomy for lung cancer had a higher risk of post-operative complications. In a study of over 5,000 people, current smokers had a 1.5-fold higher chance of suffering a pulmonary complication and 1.7 higher odds of suffering multiple complications than non-smokers or recent quitters (2 weeks to 3 months prior to surgery).76

3.15.1.3 Impact of smoking cessation

A systematic review published in 2012 explored the relationship between short-term preoperative smoking cessation and postoperative complications and concluded that at least four weeks of abstinence from smoking reduces respiratory complications, and abstinence of at least three to four weeks reduces wound-healing complications. Short-term (less than four weeks) smoking cessation did not appear to increase or reduce the risk of postoperative respiratory complications.77

A 2014 Cochrane Review examined interventions for smoking cessation preoperatively, and the impact of this on postoperative complications.78 Thirteen RCTs, with over 2000 participants, were included in the review. Intensive behavioural interventions (face-to-face counselling delivered over multiple sessions) were found to reduce the risk of any postoperative complications, and wound complications specifically. However, brief interventions did not have an impact. The authors concluded that although the ideal cessation time is not entirely clear, evidence suggests that interventions that commence at least four weeks before surgery, and that involve weekly counselling and pharmacotherapy, can reduce the risk of complications.

A study of over 6000 patients undergoing coronary artery bypass graft (CABG) surgery also found that cessation of at least four weeks’ reduced the risk of lung complications following surgery, including lung infection and reintubation.79 A further study demonstrated that smoking abstinence following CABG reduced the 5 year mortality rate by 35%.80

The Australian and New Zealand College of Anaesthetists recommend that, based on the current available evidence, anaesthetists and surgeons should not be dissuaded from advising patients to quit at any time before surgery.11

3.15.2 Drug interactions

Smoking alters the effects of a number of medications (see also Section 3.15.1.1 on interactions with anaesthetics). Doctors and other health professionals need to be aware of these interactions when medications are prescribed and also when patients quit smoking, as drug dosages may need to be adjusted.81

Drug interactions fall into two categories: (i) pharmacokinetic interactions, which occur when cigarette smoke alters a drug’s metabolism; or (ii) pharmacodynamic interactions, which occur when the physiological effects of cigarette smoke modify the physiological effects of the drug.82, 83

Pharmacokinetic interactions include increased metabolism of caffeine, heparin, warfarin, theophylline, beta-blockers (such as propranolol), a number of antipsychotic drugs (such as clozapine, chlorpromazine and olanzapine) and benzodiazepines.84-86 A meta-analysis of the interaction between smoking and warfarin, for example, found that smoking increased warfarin dosage requirements by about 12%.87 Smokers with lung cancer had increased clearance of erlotinib (a non-chemotherapy) and irinotecan (a chemotherapy), which may reduce their effectiveness in treating the lung cancer.88 Smokers with chronic obstructive pulmonary disease (COPD) gained less benefit from inhaled corticosteroids than did non-smokers; they had poorer lung function and increased exacerbations of disease.89

Although it is difficult to know which of the estimated 7,000 compounds in cigarette smoke cause these interactions,90 the polycyclic aromatic hydrocarbons are suspected. These hydrocarbons induce liver enzymes (see Chapter 3, Section 3.15.1.1) and thereby hasten the clearance of any drug (or substance) whose metabolism requires the enzymes.82, 83 Conversely, upon smoking cessation, dosages of these medications may need adjustment, as clearance will slow. For example, upon stopping smoking, smokers may need to reduce caffeine consumption.84

The pharmacokinetic interaction between tobacco smoke and the antiplatelet medication clopidogrel has been described as a ‘smoking paradox’ as there is some evidence to suggest that smokers have higher clinical responsiveness to clopidogrel than non-smokers.84 A meta-analysis of over 70,000 patients with established cardiovascular disease found that smokers taking clopidogrel had a 25% lower risk of cardiovascular events compared to an 8% reduced risk in non-smokers.91  Another study suggested that doubling the dose of clopidogrel in smokers was effective in reducing the risk of cardiovascular events, without an increase in the risk of bleeding.92 Dosages of clopidogrel and other antiplatelet medications (such as prasugrel) may need to be adjusted upon stopping smoking.93

A meta-analysis showed that smokers had significantly lower blood levels of the antipsychotic drug clozapine. The authors recommended a 30% reductions of clozapine dose for those who quit smoking94 (see also Section 7.12).

Pharmacodynamic interactions include: reduced response to corticosteroids in smokers who are asthmatic,95, 96 decreased effectiveness of benzodiazepines (a common sleeping medication) (possibly due to the stimulant effects of nicotine), slowed absorption of sub-cutaneous insulin among diabetics (possibly due to reduced blood flow to the skin, mediated by nicotine), and an increased risk of cardiovascular adverse effects in women taking oral contraceptives.82, 83

In the above examples, smoking modifies the effects of particular drugs. It has also been hypothesised that bronchodilator drugs (mainly beta-2-agonists), prescribed for people with chronic obstructive pulmonary disease (COPD), may worsen the effects of cigarette smoke. The theory is that bronchodilation improves smoke inhalation, and may increase the deposition of cigarette smoke on the lungs, thereby increasing cardiovascular disease morbidity and mortality. This hypothesis is yet to be tested.97

3.15.3 Cardiovascular disease

As detailed in Section 3.1, smoking causes cardiovascular disease, and generally, if a person continues to smoke after developing cardiovascular disease their prognosis is worse than if they had quit.

For example, a study of more than 18,000 patients who were receiving a statin drug for coronary disease found that over a five-year period those who continued to smoke had about a 50% higher chance of a major cardiovascular event (heart attack, stroke, cardiac arrest or death) than patients who quit.98  However, a more recent meta-analysis found that the risk of major cardiovascular events in people using statins was similar for smokers and non-smokers.99

Poorer treatment outcomes have been reported for people who continue to smoke after coronary artery bypass grafting100 or a diagnosis of heart failure,101 compared with people who quit.

A 2019 meta-analysis involving over 120,000 patients undergoing either percutaneous coronary intervention (i.e. placement of a stent, a small device to open up an artery) or CABG found that smokers had a higher risk of all-cause mortality compared to non-smokers.102 However, there was no statistically significant difference in the rate of heart attacks, all cardiovascular events or cardiovascular deaths . The increased risk of all-cause mortality was also true of ex-smokers, compared to non-smokers.

3.15.4 Cancer

As detailed in Section 3.5, smoking causes numerous cancers.

The 2014 Surgeon General’s report was the first in its series to review the associations between cigarette smoking and health outcomes in cancer patients and survivors. It concluded that smoking causes adverse health outcomes in people with cancer, while cessation improves their prognosis. Smoking increases all-cause mortality and cancer-specific mortality in cancer patients and survivors, and increases the risk of second primary cancers that are caused by cigarette smoking, including lung cancer. Smoking may increase the risk of recurrence, result in a poorer response to treatment, and increase treatment-related toxicity.103

A 2018 review published by the World Health Organization identified some of the mechanisms by which smoking affects outcomes of cancer treatment.104 These mechanisms include increased cancer cell proliferation, migration and metastasis (development of secondary cancers), acceleration of systemic clearance of cancer therapies (potentially impacting efficacy of cancer treatment), increased complications associated with treatment, and an increased risk of co-morbidities related to tobacco.

The review also reinforced findings from the Surgeon General’s report, regarding the impact of smoking on cancer outcomes, including increased risk of all-cause mortality, cancer-specific mortality, recurrence, and reduced quality of life. Specifically, this included studies of patients with lung cancer, head and neck cancers, bladder cancer and breast cancer.104

A 2018 meta-analysis of patients with colorectal cancer found that current and former smokers had lower overall survival compared with never smokers. In the same study, smoking cessation, compared to current smoking, was linked with an improvement in overall and colorectal cancer-specific survival.105 Smoking has also been identified as a risk factor for superficial surgical site resections in patients undergoing rectal cancer resection.106

More severe pain has been associated with smoking in patients with cancer,107 and specifically for lung cancer108 and head and neck cancer.109 This may be because of the decreased effectiveness of opioids (due to increased drug metabolism caused by cigarette smoke components) described in Chapter 3, Section 3.15.1.1, and failure to increase the dose in response.

Smokers with bladder cancer who had surgery to remove their bladder had poorer outcomes than non-smokers. They had an increased risk of overall mortality, cancer-specific mortality and recurrence of bladder cancer.110

A meta-analysis showed that smoking was associated with increased risk of complications, such as skin reactions and reduced pulmonary function, for people with breast cancer having adjuvant radiotherapy (radiotherapy after initial treatment, such as surgery).111

Stem cell transplantation can be an effective treatment for some blood cancers. In a cohort study, smoking was found to be an independent risk factor for mortality within five years after stem cell transplantation.112

A 2019 meta-analysis did not find any difference in response to immunotherapy (for treatment of advanced solid organ cancers) between ever smokers and never smokers.113 However, since this report, numerous studies and meta-analyses have found that immunotherapy using PD-1 or PD-L1 inhibitors (a major class of immunotherapies) had greater efficacy for smokers than non-smokers. Never smokers with non-small cell lung cancer (NSCLC) treated with pembrolizumab (a PD-1 inhibitor) had higher risk of disease progression and death compared to smokers.114 Smokers with metastatic urothelial carcinoma treated with pembrolizumab also had a lower risk of disease progression and mortality compared to non-smokers.115 A meta-analysis of high quality trials testing any PD-1/PD-L1 inhibitor on any cancer found similar results. Non-smokers had no increase in survival with the immunotherapies above the benefit of chemotherapy, however smokers benefitted more from immunotherapy than from chemotherapy.116 A similar meta-analysis also found that current or former smokers had an increase in progression-free survival and overall survival with PD-1/PD-L1 immunotherapy compared to chemotherapy, irrespective of cancer type.117 It should be noted that a greater benefit of PD-1/PD-L1 immunotherapy over chemotherapy for smokers does not necessarily mean that smokers have increased survival from these cancers overall, rather that PD-1/PD-L1 immunotherapy is a more effective treatment for smokers than chemotherapy in specific circumstances. Smoking causes an increased risk of mortality for people with cancer and an increased risk in a second primary cancer.103

Smoking cessation improves outcomes in cancer patients. Cessation is associated with  an improved quality of life (in patients with lung or head and neck cancers), reduced risk of cancer-specific mortality (in patients with breast cancer) and improvement in survival (for patients with lung cancer, head and neck, colorectal and bladder cancer).118 Patients who stop smoking also experience reduced treatment-related toxicity.118, 119

A 2019 retrospective study on patients with primary lung cancer who had undergone lung resection, found that smoking cessation reduced the risk of lung complications following surgery and mortality rate at 90 days. The longer the period of cessation, the lower the risk of lung complications.120

For an overview of smoking cessation interventions for people with cancer, see Section 7.19.5.

3.15.5 Treatment of infertility including assisted reproduction

See Section 3.6.3.

3.15.6 Other conditions

A meta-analysis published in 2011 found that in patients receiving long-term haemodialysis (use of an artificial kidney machine to clean the blood) or peritoneal dialysis (an alternative to haemodialysis, uses the lining of the abdomen to clean the blood), smoking increased the death rate (all-cause mortality) by 65%.134

A 2019 meta-analysis and systematic review found that burns patients who smoke have higher rates of complications compared to non-smokers, including an increased risk of intubation (insertion of a tube through the mouth to support artificial breathing) and skin infections.135

For the effects of smoking on contraception, see Section 3.6.4.


Relevant news and research

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References

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33. Bedard NA, DeMik DE, Owens JM, Glass NA, DeBerg J, et al. Tobacco use and risk of wound complications and periprosthetic joint infection: A systematic review and meta-analysis of primary total joint arthroplasty procedures. Journal of Arthroplasty, 2019; 34(2):385-96 e4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30385090

34. Cancienne JM, Brockmeier SF, and Werner BC. Tobacco use is associated with increased rates of infection and revision surgery after primary superior labrum anterior and posterior repair. Journal of Shoulder and Elbow Surgery, 2016; 25(11):1764-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27262413

35. Carender CN, DeMik DE, Bedard NA, Glass NA, and Brown TS. Increased risk of short-term complications in smokers undergoing primary unicompartmental knee arthroplasty. Journal of Knee Surgery, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32898899

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