Several drugs and medical devices used in the field of intensive care in Japan are not internationally approved; the development of these drugs and devices is sometimes referred to as “Galapagosization.” The present article reviews the approval trials, including minutes of public review by regulatory authorities, for ICU treatments unique to Japan that have been approved since the 2000s. Sivelestat, a neutrophil elastase inhibitor, was approved for the treatment of ARDS in Japan in 2002. Although the initial phase Ⅲ double-blinded trial failed to demonstrate efficacy, an additional single-arm trial was conducted and the drug was approved based on the number of ventilator-free days being larger than the numbers for the initial phase Ⅲ trial and the ARDS network trials. The primary endpoint of a phase Ⅲ trial for thrombomodulin, an anticoagulant for the treatment of DIC, was the DIC resolution rate using a dichotomization of the DIC diagnostic score. Thrombomodulin was approved in 2008 because of the superiority of its DIC resolution rate on day 7, but no advantage in 28-day mortality or the DIC diagnostic score was seen. In global trials, sivelestat was inferior to a control group in terms of 180-day mortality and thrombomodulin failed to show an advantage for 28-day mortality, so neither of these drugs were approved internationally. A single-arm study of a cytokine-adsorbing hemofilter using the AN69ST membrane was conducted in patients with septic shock. The 28-day survival rate was higher than the predicted survival rate derived from the APACHE Ⅱ score, and in 2014, the hemofilter was approved as the world's first treatment for sepsis to be covered by a public insurance program. In Japanese clinical trials of drugs and medical devices, statistical analyses that are not emphasized in other countries are sometimes performed and can lead to drug or device approval, as shown by the emphasis on surrogate endpoints and single-arm trials and the de-emphasis of mortality rates.

View full abstract

Objective: Augmented renal clearance (ARC) has been reported in critically ill patients with trauma and sepsis. In this study, we investigated the occurrence of ARC following major hepatobiliary-pancreatic (HBP) surgery, which has rarely been reported. Methods: We conducted a case-control study to investigate factors associated with ARC development following HBP surgery and examined methods for evaluating renal function. Patients who underwent HBP surgery and were admitted to our ICU between October 2018 and March 2021 were retrospectively reviewed. Creatinine clearance (CrCl) by 6-hour urine collection ≥130 mL/ min/1.73 m² was defined as ARC. Results: In total, 144 patients were evaluated. The incidence of ARC was 38.2% (n=55). Multivariate analysis showed that age, estimated glomerular filtration rate (eGFR) before surgery, and intraoperative transfusion of red blood cells were associated with ARC incidence. In the case of ARC, a proportional error was found between the eGFR and CrCl. Conclusion: ARC occurs at a high rate after major HBP surgery. The evaluation of renal function using CrCl is necessary to recognize ARC development.

View full abstract

An 80-year-old woman was brought to the emergency room with acute coronary syndrome-induced cardiogenic shock. She underwent emergency catheterization, following which she was managed in the intensive care unit with ventilatory support, intra-aortic balloon pumping (IABP), and inotropic drugs. She continued to have prolonged cardio-genic shock in the postoperative period. A systolic murmur was heard at the left sternal margin in the fourth intercostal space. An echocardiography showed a sigmoid septum and accelerated blood flow in the left ventricular outflow tract, suggesting a tract obstruction (LVOTO). Therefore, IABP and inotropic drugs were discontinued, following which her hemodynamics improved. A repeat echocardiography showed no evidence of accelerated blood flow or pressure gradient in the left ventricular outflow tract despite the presence of a sigmoid septum. In conclusion, an elderly woman with a sigmoid septum suffered a myocardial infarction that caused compensatory basal wall motion in the heart, resulting in dynamic LVOTO. The use of IABP and inotropic drugs increased the pressure gradient in the left ventricular outflow tract, exacerbating her altered hemodynamics.

View full abstract

[in Japanese]

View full abstract

[in Japanese]

View full abstract

[in Japanese]

View full abstract