Upsala Journal of Medical Sciences. 2011; 116: 115–123 ORIGINAL ARTICLE Critical diaphragm failure in sudden infant death syndrome PONTUS MAX AXEL SIREN & MATTI JUHANI SIREN JGK Memorial Research Library, Helsinki, Finland Abstract Sudden infant death syndrome (SIDS) is the leading cause of death in infants between the ages of 1 and 12 months in developed countries. SIDS is by deﬁnition a diagnosis of exclusion, and its mechanism of action is unknown. The SIDS– Critical Diaphragm Failure (CDF) hypothesis postulates that the cause of death in SIDS is respiratory failure caused by CDF. Four principal risk factors contribute to CDF in young infants: undeveloped respiratory muscles, non-lethal infections, prone resting position, and REM sleep. Even relatively minor infections can cause an acute and signiﬁcant reduction in diaphragm force generation capacity that in conjunction with other risk factors can precipitate CDF. CDF-induced acute muscle weakness leaves few, if any pathological marks on the affected tissue.Understanding the underlying mechanism of SIDS may help in formulating new approaches to child care that can help to further reduce the incidence of SIDS. Key words: sudden infant death syndrome (SIDS), infection, diaphragm, pediatrics Introduction It has been recognized since antiquity that seemingly healthy infants can die suddenly and for no obvious reason during their sleep. Indeed, the Bible makes reference to such an incidence in the First Book of Kings. One of the ﬁrst known medical autopsies of an apparent sudden infant death syndrome (SIDS) case was conducted by Samuel Fearn and published in the Lancet in 1834 (1). In his short communica- tion, Fearn asked a simple question that has frus- trated generations of doctors and researchers: ‘what was the cause of death?’ Over 175 years later the question is still unanswered (2). SIDS has been the target of an enormous research effort, with over 9,500 scientiﬁc articles published on the subject (3), but it remains one of the most mysterious disorders in medicine. Our primary research interest, cancer cachexia (4), gave us a singular perspective into SIDS, and we formulated the SIDS–Critical Diaphragm Failure (CDF) hypothesis to answer Fearn’s original ques- tion. It is perhaps surprising that research areas unrelated to SIDS could contribute meaningfully to the understanding of this complex syndrome, and yet there is a large body of experimental and clinical evidence that suggests that the cause of death in SIDS is respiratory failure caused by CDF. We argue that four factors contribute to CDF in SIDS: undeveloped respiratory muscles, non-lethal infections, prone resting position, and REM sleep. Infants younger than 6 months have undeveloped respiratory muscles that are susceptible to CDF, because even minor infections can precip- itate a signiﬁcant reduction in the diaphragm force generation capacity. The prone sleeping position signiﬁcantly increases the diaphragm work-load, and the intercostal muscles that usually provide respiratory support are inactivated in REM sleep. The non-monotonic mortality rate of SIDS is explained by the passive maternal antibodies that effectively attenuate infections during the ﬁrst month of life, and rapid development of the infant dia- phragm that reaches the same ﬁber composition and pressure generation capacity as the adult muscle approximately 6 months post partum. Correspondence: Pontus Max Axel Siren, JGK Memorial Research Library, Snellmanin k 15, 00170, Helsinki, Finland. Fax: +358 9 241 40 55. E-mail: pontusmax@hotmail.com (Received 2 December 2010; accepted 10 December 2010) ISSN 0300-9734 print/ISSN 2000-1967 online 2011 Informa Healthcare DOI: 10.3109/03009734.2010.548011