LETTERS (3), rather than a seasonally adjusted value. It should also be pointed out that differences between studies could also reflect variations in the time of gestation when vitamin D levels were measured. For example, the Avon Longitudinal Study of Parents and Children study measured 25(OH)D at 34 weeks’ gestation (4), a time when the lung is relatively mature compared with 16–20 weeks’ gestation, as was the case in our study. Perret and Lodge raise an important point regarding the bioavailable fraction of 25(OH)D. We measured total 25(OH)D, which may have introduced an additional level of variation (error) into our data; however, it is unlikely to have changed the direction of our findings. The importance of considering ethnicity in population studies of vitamin D is also noted. The Western Australia Pregnancy cohort used for our study is known to have a high proportion of whites (.80%), so it is unlikely that ethnicity had a major effect on our analysis. Further analysis of the effect of vitamin D deficiency on postnatal lung outcome at different stages of gestation is certainly warranted, along with consideration of the effect of ethnicity and genetic polymorphisms on the bioavailability of circulating 25(OH)D. Author disclosures are available with the text of this letter at www.atsjournals.org.

Diffuse Alveolar Hemorrhage, Anesthesia, and Cannabis To the Editor: We read with interest the letter submitted by Kim and colleagues entitled “Diffuse Alveolar Hemorrhage Induced by Sevoflurane” (1). The letter reported and commented on the experience of a 31-year-old man with a past history of cannabis use who developed pulmonary edema and hemoptysis 45 minutes into the postoperative period after perirectal pilonidal cyst excision. The authors came to the ultimate conclusion that this was a case of diffuse alveolar hemorrhage related to sevoflurane administration. We propose that the patient’s alveolar hemorrhage is more likely attributable to negative pressure pulmonary edema in conjunction with the patient’s cannabis use. We have chosen to use the term cannabis in place of “marijuana,” in accordance with National Cannabis Prevention and Information Centre recommendations. Negative pressure pulmonary edema is a condition that occurs most frequently surrounding anesthesia, although a dyssynchrony between the patient and a ventilator has also been cited as a cause in the intensive care unit. The incidence of negative pressure pulmonary edema is believed to be 0.05–0.1% for patients undergoing general anesthesia. It has been suggested that 50% of these episodes occur in the postoperative recovery area (2). Edema develops as a consequence of an excessive pressure gradient between the capillary space and the alveolar space caused by a negative intrathoracic pressure-induced increase in right ventricular filling and a decrease in left ventricular ejection (3). Although rare, negative pressure pulmonary edema has been associated with hemoptysis (4). Use of the term negative pressure pulmonary hemorrhage has been suggested for this


Graeme R. Zosky, Ph.D. University of Tasmania Hobart, Tasmania, Australia Prue H. Hart, Ph.D. Andrew J. O. Whitehouse, Ph.D. Graham L. Hall, Ph.D. University of Western Australia Crawley, Western Australia, Australia

References 1 Zosky GR, Hart PH, Whitehouse AJO, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Ramankutty P, de Klerk NH, Miller M, Fenech M, O’Callaghan N, Armstrong BK, Milne E. Ultraviolet radiation exposure and serum vitamin D levels in young children. J Paediatr Child Health 2014;50:713–720. 3 Pramyothin P, Holick MF. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol 2012; 28:139–150. 4 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180–1188. Copyright © 2014 by the American Thoracic Society

variant (3). For alveolar hemorrhage to develop, there must also be mechanical damage to the alveolar epithelial lining. We believe the patient’s cannabis use could have contributed to this damage, through both the pulmonary injury and anticoagulation. Similar to tobacco, cannabis smoking has been linked to visual and histological evidence of airway inflammation, edema, and increased alveolar permeability (5). In addition to this, cannabis has been implicated in anticoagulant effects. It has been shown that cannabis sativa, tetrahydrocannabinol, and cannabinol cause inhibition of thrombin-driven clot formation in a rat model (6). It should be noted that there are many variables in cannabis’ effects on lung function that remain understudied: the effect of tetrahydrocannabinol content in each use, the route of administration (cigarette vs. water pipe vs. vaporizer), and the complicated relationship between acute and chronic use on bronchodilation and constriction. The authors postulate that sevoflurane was the causative agent in their case but were able to find only one other case report in support of this hypothesis. The patients described in both case reports engaged in recreational drug use. Diffuse alveolar hemorrhage has been shown to occur with crack cocaine as well. In conclusion, we suggest that instead of the highly unlikely event of sevoflurane-induced pulmonary hemorrhage, the cause is more likely to be related to negative pressure pulmonary edema that was rendered hemorrhagic by antecedent lung injury and coagulopathy attributable to recreational drug use. The increase in legalized cannabis use in the United States may present an opportunity to further investigate functional coagulation effects in the setting of cannabis use. It would also be interesting to see whether there is an increased incidence of possible negative pressure pulmonary edema with the newer formulations of cannabis compared with traditional, naturally grown cannabis. AnnalsATS Volume 11 Number 8 | October 2014

LETTERS Author disclosures are available with the text of this letter at www.atsjournals.org.


2 Louis PJ, Fernandes R. Negative pressure pulmonary edema. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:4–6. 3 Schwartz DR, Maroo A, Malhotra A, Kesselman H. Negative pressure pulmonary hemorrhage. Chest 1999;115:1194–1197. 4 Broccard AF, Liaudet L, Aubert JD, Schnyder P, Schaller MD. Negative pressure post-tracheal extubation alveolar hemorrhage. Anesth Analg 2001;92:273–275. 5 Gates P, Jaffe A, Copeland J. Cannabis smoking and respiratory health: consideration of the literature. Respirology 2014;19:655–662. 6 Coetzee C, Levendal R-A, van de Venter M, Frost CL. Anticoagulant effects of a Cannabis extract in an obese rat model. Phytomedicine 2007;14:333–337.

1 Kim CA, Liu R, Hsia DW. Diffuse alveolar hemorrhage induced by sevoflurane [letter]. Ann Am Thorac Soc 2014;11:853–855.

Copyright © 2014 by the American Thoracic Society

Andrew W. Murray, M.B., Ch.B. Jan D. Smith, M.B., Ch.B., D.T.M.&H. James W. Ibinson, M.D., Ph.D. University of Pittsburgh Department of Anesthesiology Pittsburgh, Pennsylvania



Diffuse alveolar hemorrhage, anesthesia, and cannabis.

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