Table 1.

History of carbon monoxide inhalational clinical trials including healthy volunteers and patients. The lower part represents the studies, which have been withdrawn for various reasons. (This list is not exhaustive)

Ref.	Year	First author	Number of participants	Carbon monoxide dose	CO-Hb	Outcome/marker
52	1973	R.D. Steward	Not reported	100 ppm for 8 h	11–13%	Feasibility study
53	1975	J.E. Peterson	22 volunteers	50, 100, and 200 ppm for 5.25 h	1–20%	Feasibility study, check of Coburn-Forster-Kane equation
55	1997	M. Hausberg	10 volunteers	30 min of 1000 ppm followed by 30 min of 100 ppm	8.3 ± 0.5%	Acute sympathetic and hemodynamic effects, no differences between groups
54	2001	Ren	11 subjects	4000 ppm until CO-Hb = 10%	9.7 ± 0.1	Respiratory response to prolonged hypoxia, no differences between groups
56	2001	Zevin	12 healthy smokers	1200–1500 ppm and smoking of at least 20 cigarettes per day for 7 days	5 ± 1%	No differences in blood pressure or respiratory rate; analysis of platelet factor 4 and urine epinephrine and norepinephrine
58	2005	Mayr	9 volunteers	500 ppm for 1 h after intravenous LPS injection (2 ng/kg BW)	6.5–7.7%	TNF, IL-1, IL-6, IL-8 concentrations in plasma showed no differences
62	2005	Resch	15 volunteers	500 ppm for 1 hour	8.5 ± 0.9%	Significant increase in retinal and choroidal blood flow
59	2007	Bathoorn	20 COPD patients	100–125 ppm CO for 2 h on 4 consecutive days	4.5%	Trend in the reduction of sputum eosinophils, improvement in response to metacholine
57	2009	Rhodes	6 subjects	100 ppm for 1 h for 5 days	3.3 ± 0.6%	Significant increase in SOD, HO-1, mitofusin, ATPase-6 and COX-1 proteins due to CO inhalation
60	2015	Pecorella	19 subjects	200 ppm for 1 h for 5 days	5.4 ± 0.8%	Significant increase in muscle citrate synthase, mitochondrial density and GLUT4
61	2016	Ryan	18 volunteers	1.2 mL/kg BW for 30 s for 10 days	4.4 ± 0.4%	No changes in haemoglobin mass, aerobic performance or peak power exercise tolerance
				Studies withdrawn
	2007	NCT00531856	%	5.97 mg/L of carbon monoxide in 30% oxygen post transplantation (3 different doses)	n.a.	Primary outcome: Evaluate the safety and tolerability, secondary: incidence of delayed graft dysfunction (study withdrawn)
	2012	NCT01523548	%	150 ppm for 3 h for 3 weeks	n.a.	Primary outcome: Evidence of a decrease in pulmonary vascular resistance post-therapy (Study withdrawn)
	2010	NCT01050712	%	Depending on a healthy control group	n.a.	Primary outcome: incidence and duration of postoperative ileus (Study withdrawn)
	2012	NCT01727167	%	200 ppm for 1 h	n.a.	Primary outcome: Biochemical Markers for Mitochondrial Biogenesis in aortic valve surgery (Study withdrawn)