Neurocritical Care

, Volume 14, Issue 1, pp 77–83

Transdermal Nicotine Replacement Therapy in Cigarette Smokers with Acute Subarachnoid Hemorrhage

  • David B. Seder
  • J. Michael Schmidt
  • Neeraj Badjatia
  • Luis Fernandez
  • Fred Rincon
  • Jan Claassen
  • Errol Gordon
  • Emmanuel Carrera
  • Pedro Kurtz
  • Kiwon Lee
  • E. Sander Connolly
  • Stephan A. Mayer
Original Article



We evaluated the safety of nicotine replacement therapy (NRT) in active smokers with acute (aneurysmal) subarachnoid hemorrhage (SAH).


A retrospective observational cohort study was conducted in a prospectively collected database including all SAH patients admitted to an 18-bed neuro-ICU between January 1, 2001 and October 1, 2007. Univariate and multivariable models were constructed, employing stepwise logistic regression. The primary endpoint was 3-month mortality. Delayed cerebral ischemia (DCI) due to vasospasm, angiographic and TCD evidence of vasospasm, and delirium were secondary endpoints.


Active cigarette smokers admitted with SAH included 128 that received NRT and 106 that did not. Patients were well-matched for age, admission Hunt-Hess Grade, radiographic findings, and APACHE II scores, but those who received NRT were more likely to be heavy smokers (>10 cigarettes daily), diabetic, heavy alcohol users, and to have cerebral edema on admission. NRT was associated in multivariate analysis with a lower risk of death at 3 months (OR 0.12, 95% CI 0.04–0.37, P < 0.001). There were no differences in the frequency of DCI and most other medical complications, but delirium (19 vs. 9%, P = 0.006) and seizures (9 vs. 2%, P = 0.024) were more common in patients who received NRT.


Despite vasoactive properties, administration of NRT among active smokers with acute SAH appeared to be safe, with similar rates of vasospasm and DCI, and a slightly higher rate of seizures. The association of NRT with lower mortality could be due to chance, to uncontrolled factors, or to a neuroprotective effect of nicotine in active smokers hospitalized with SAH, and should be tested prospectively.


Subarachnoid hemorrhage Hemorrhagic stroke Nicotine Neurocritical care Aneurysm 


  1. 1.
    Anderson CS, Feigin V, Bennett D, et al. Active and passive smoking and the risk of subarachnoid hemorrhage. Stroke. 2004;35:633–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Weir BKA, Kongable GL, Kassell NF, et al. Cigarette smoking as a cause of aneurysmal subarachnoid hemorrhage and risk for vasospasm: a report of the Cooperative Aneurysm Study. J Neurosurg. 1998;89:405–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Koskinen LOD, Blomstedt PC. Smoking and non-smoking tobacco as risk factors in subarachnoid hemorrhage. Acta Neurol Scand. 2006;114:33–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Lasner TM, Weil RJ, Riina HA, et al. Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1997;87:381–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Krishnamurthy S, Kelleher JP, Lehman EB, Cockroft KM. Effects of tobacco dose and length of exposure on delayed neurological deterioration and overall clinical outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;61:475–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Mayer SA, Chong JY, Ridgeway E, Min C, Commichau C, Bernardini GL. Delirium from nicotine withdrawal in neuro-ICU patients. Neurology. 2001;57:551–3.PubMedGoogle Scholar
  7. 7.
    Ballard J, Kreiter KT, Claassen J, Kowalski RG, Connolly ES, Mayer SA. Risk factors for continued cigarette use after subarachnoid hemorrhage. Stroke. 2003;34:1859–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Molyneux A, Lewis S, Leivers U, et al. Clinical trial comparing nicotine replacement therapy (NRT) plus brief counselling, brief counseling alone, and minimal intervention on smoking cessation in hospital inpatients. Thorax. 2003;58:484–8.CrossRefPubMedGoogle Scholar
  9. 9.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association; 1994.Google Scholar
  10. 10.
    Rudolph JL, Jones RN, Rasmussen LS, et al. Independent vascular and cognitive risk factors for postoperative delirium. Am J Med. 2007;120(9):807–13.CrossRefPubMedGoogle Scholar
  11. 11.
    Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–62.CrossRefPubMedGoogle Scholar
  12. 12.
    Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard GR, Inouye SK. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892–900.CrossRefPubMedGoogle Scholar
  13. 13.
    Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care. 2005;9:R375–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Huhtasaari F, Asplund K, Lundberg V, Stegmayr B, Wester PO. Tobacco and myocardial infarction: is snuff less dangerous than cigarettes? BMJ. 1992;305:1252–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Huhtasaari F, Lundberg V, Eliasson M, Janlert U, Asplund K. Smokeless tobacco as a possible risk factor for myocardial infarction. A population based study in middle aged men. J Am Coll Cardiol. 1999;34:1784–90.CrossRefPubMedGoogle Scholar
  17. 17.
    Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med. 1996;335:1792–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Meine TJ, Patel MR, Washam JB, Pappas PA, Jollis JG. Safety and effectiveness of transdermal nicotine patch in smokers admitted with acute coronary syndromes. Am J Cardiol. 2005;95:976–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997;29:1422–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee AH, Afessa B. The association of nicotine replacement therapy with mortality in a medical intensive care unit. Crit Care Med. 2007;35:1517.CrossRefPubMedGoogle Scholar
  21. 21.
    Cartin-Ceba R, Afessa B. Nicotine replacement therapy in critically ill patients: a prospective observational cohort study. Crit Care Med. 2009;37 Suppl 12:A8.Google Scholar
  22. 22.
    Paciullo CA, Short MR, Steinke DT, Jennings HR. Impact of nicotine replacement therapy on postoperative mortality following coronary artery bypass graft surgery. Ann Pharmacother. 2009;43:1197–202.CrossRefPubMedGoogle Scholar
  23. 23.
    Mundal H, Hjemdahl P, Gjesdal K. Acute effects of low dose nicotine gum on platelet function in nonsmoking hypertensive and normotensive men. Eur J Clin Pharmacol. 1995;47:411–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol. 1993;22:1159–67.CrossRefPubMedGoogle Scholar
  25. 25.
    Rangemark C, Benthin G, Granstrom EF, Persson L, Winell S, Wennmalm A. Tobacco use and urinary excretion of thromboxane A2 and prostacyclin metabolites in women stratified by age. Circulation. 1992;86:1495–500.PubMedGoogle Scholar
  26. 26.
    Gerzanich V, Zhang F, West GA, Simard JM. Chronic nicotine alters NO signaling of Ca2+ channels in cerebral arterioles. Circ Res. 1991;88:359.Google Scholar
  27. 27.
    Davis JW, Shelton L, Eigenberg DA, Hignite CE, Watanabe IS. Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets. Clin Pharmacol Ther. 1985;37:529–33.CrossRefPubMedGoogle Scholar
  28. 28.
    Lin SJ, Hong CY, Chang MS, Chiang BN, Chien S. Long-term nicotine exposure increases aortic endothelial cell death and enhances transendothelial macromolecular transport in rats. Arterioscler Thromb. 1992;12:1305–12.PubMedGoogle Scholar
  29. 29.
    Claassen J, Kreiter KT, Kowalski RG, et al. Effect of acute physiologic derangements on outcome after subarachnoid hemorrhage. Crit Care Med. 2004;32:832–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Claassen J, Carhuapoma JR, Kreiter KT, et al. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors and impact on outcome. Stroke. 2002;33:1225–32.CrossRefPubMedGoogle Scholar
  31. 31.
    Naidech AM, Jovanovic B, Wartenberg KE, et al. Higher hemoglobin is associated with improved outcome after subarachnoid hemorrhage. Crit Care Med. 2007;35:2383–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Schmidt JM, Wartenberg KE, Fernandez A, et al. Frequency and clinical impact of asymptomatic cerebral infarction due to vasospasm after subarachnoid hemorrhage. J Neurosurg. 2008;109:1052–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method: a new method for detection of delirium. Ann Intern Med. 1990;113:941–8.PubMedGoogle Scholar
  34. 34.
    Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical complications on outcome after subarachnoid hemorrhage. Crit Care Med. 2006;34:617–23.CrossRefPubMedGoogle Scholar
  35. 35.
    Kox M, Hoedemaekers AW, Pickkers P, van der Hoeven JG, Pompe JC. A possible role for the cholinergic anti-inflammatory pathway in increased mortality observed in critically ill patients receiving nicotine replacement therapy. Crit Care Med. 2007;35(10):2468–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Bergstrom HC, McDonald CG, French HT, Smith RF. Continuous nicotine administration produces selective, age-dependent structural alteration of pyramidal neurons from prelimbic cortex. Synapse. 2008;62(1):31–9.CrossRefPubMedGoogle Scholar
  37. 37.
    McDonald CG, Eppolito AK, Brielmaier JM, Smith LN, Bergstrom HC, Lawhead MR, Smith RF. Evidence for elevated nicotine-induced structural plasticity in nucleus accumbens of adolescent rats. Brain Res. 2007;1151:211–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Benowitz NL. Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther. 2008;83:531–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Fratiglioni L, Wang HX. Smoking and Parkinson’s and Alzheimer’s disease: review of the epidemiological studies. Behav Brain Res. 2000;113:117–20.CrossRefPubMedGoogle Scholar
  40. 40.
    Picciotto MR, Zoli M. Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Front Biosci. 2008;13:492–504.CrossRefPubMedGoogle Scholar
  41. 41.
    Powers KM, Kay DM, Factor SA, et al. Combined effects of smoking, coffee, and NSAIDs on Parkinson’s disease risk. Mov Disord. 2008;23:88–95.CrossRefPubMedGoogle Scholar
  42. 42.
    Parain K, Hapdey C, Rousselet E, Marchand V, Dumery B, Hirsch EC. Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin. Brain Res. 2003;984:224–32.CrossRefPubMedGoogle Scholar
  43. 43.
    Quik M, Bordia T, O’Leary K. Nicotinic receptors as CNS targets for Parkinson’s disease. Biochem Pharmacol. 2007;74:1224–34.CrossRefPubMedGoogle Scholar
  44. 44.
    Copeland RL Jr, Das JR, Kanaan YM, Taylor RE, Tizabi Y. Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity. Neurotox Res. 2007;12:61–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Akaike A, Tamura Y, Yokota T, Shimohama S, Kimura J. Nicotine-induced protection of cultured cortical neurons against N-methyl-d-aspartate receptor-mediated glutamate cytotoxicity. Brain Res. 1994;644:181–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Marin P, Maus M, Desagher S, Glowinski J, Premont J. Nicotine protects cultured striatal neurons against N-methyl-d-aspartate receptor-mediated toxicity. Neuroreport. 1994;5:1977–80.CrossRefPubMedGoogle Scholar
  47. 47.
    Garrido R, Malecki A, Hennig B, Toborek M. Nicotine attenuates arachadonic acid-induced neurotoxicity in cultured spinal cord neurons. Brain Res. 2000;861:59–68.CrossRefPubMedGoogle Scholar
  48. 48.
    Park HJ, Lee PH, Ahn YW. Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci. 2007;26:79–89.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • David B. Seder
    • 1
  • J. Michael Schmidt
    • 2
  • Neeraj Badjatia
    • 2
  • Luis Fernandez
    • 2
  • Fred Rincon
    • 2
  • Jan Claassen
    • 2
  • Errol Gordon
    • 2
  • Emmanuel Carrera
    • 2
  • Pedro Kurtz
    • 2
  • Kiwon Lee
    • 2
  • E. Sander Connolly
    • 3
  • Stephan A. Mayer
    • 2
    • 3
  1. 1.Department of Critical Care Services, Neuroscience InstituteMaine Medical CenterPortlandUSA
  2. 2.Division of Critical Care NeurologyColumbia Presbyterian Medical CenterNew YorkUSA
  3. 3.Department of Neurological SurgeryColumbia Presbyterian Medical CenterNew YorkUSA

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