Extensive use of vasodilator agents and functional echocardiography to monitor extremely-low-birth-weight infants in Japan

1 Introduction

Previous national surveys of perinatal medicine in Japan revealed a marked improvement in the prognosis of extremely-low-birth-weight infants (ELBWIs) [1]. The improvements in prognosis were largely due to the progression of medical techniques. Although circulatory management is one of the most important factors in the clinical management of ELBWIs, our understanding of the current practices at each institution were based on long-held views and individual reports from various institutions. In order to investigate the actual strategy of circulatory management of ELBWIs in Japan, we conducted two national surveys about perinatal circulatory management in 2006 and 2011.

2 Methods

In 2006, the questionnaire was either emailed or mailed to all neonatal intensive care unit (NICU) directors who were members of the Japanese Neonatologist Association. In 2011, the questionnaire was emailed to all of the NICU directors that were sampled in 2006 as well as NICU directors who belonged to the Japanese Society for Perinatal Circulatory Management.

The questionnaire items were divided into three major categories: indexes for circulatory management, policy of blood pressure control, and manner of use for cardiovascular agents. The original questionnaire in 2006 was slightly modified to include additional items in 2011. The questionnaire items are listed in Tables 1 and 2. The index for circulatory management on the initial questionnaire in 2006 included vital signs, physical findings, and examinations, but it was amended in 2011 to include items about echocardiography. To explore the policies that govern blood pressure control, the surveys collected information about the methods used to measure blood pressure and target blood pressure values. Finally, the surveys examined manner of use for cardiovascular agents. The initial questionnaire included items on the use and expected effects of cardiovascular agents, such as catecholamines. The questionnaires that were used in 2011 were modified to include the use and indication of vasodilator agents, the use of steroid hormones in acute stages, and the prophylactic use of indomethacin.

3 Results

The number of institutions that were surveyed increased from 80 institutions in 2006 to 100 institutions in 2011. The details of the institutions are provided in Table 3. Forty-seven institutions participated in both surveys: 15 academic medical centers, 6 children’s hospitals, and 26 general hospitals.

In terms of circulatory management, more than 90% of the surveyed institutions selected “blood pressure” and “urinary output” as important indexes for circulatory management (73/80 and 79/80 in 2006, and 93/100 and 99/100 in 2011). Meanwhile, the use of the “edema” index increased from 55% (44/80) in 2006 to 75% (75/100) in 2011. In the category of examinations, “echocardiography” was used at approximately 95% of the institutions in both 2006 and 2011 (75/80 in 2006 and 95/100 in 2011). Although “electrolytes” were selected as an important measure by approximately 80% of the surveyed institutions (61/80 in 2006 and 80/100 in 2011), the number of institutions that selected “blood gas analysis”, “chest X-ray,” and “blood urea nitrogen and creatinine” decreased from 98% (78/80), 78% (62/80), and 43% (34/80) institutions in 2006 to 79% (79/100), 57% (57/100), and 24% (24/100) institutions in 2011, respectively. In contrast, the number of institutions that selected “lactate” increased from 50% (40/80) institutions in 2006 to 66% (66/100) in 2011 (Fig. 1a).

In both 2006 and 2011, approximately 40% of the surveyed institutions indicated that echocardiography was conducted twice a day during acute phases (35/80 in 2006 and 40/100 in 2011). However, the frequency of echocardiography increased in 2011 compared to 2006 (Fig. 1b). The 2011 survey investigated echocardiographic examinations in greater detail. Over 90% of the institutions selected “left ventricular internal end-diastolic dimension (LVIDd),” “left ventricular ejection fraction (LVEF),” and “left atrial-to-aortic root diameter ratio (LA/Ao)” as important parameters. “Mitral valve regurgitation (MR)” and “tricuspid valve regurgitation (TR)” were chosen by approximately 80% of the institutions. Additionally, “mean velocity of circumferential fiber shortening (mVcfc)” and “left ventricular end-systolic wall stress (ESWS)” were chosen by about 60% of the institutions (Fig. 1c). Finally, in all of the NICU’s surveyed, echocardiographic examinations were performed by neonatologists.

In terms of blood pressure control policies, 25% (20/80) of the institutions surveyed in 2006 selected “non-invasive blood pressure measurement” as the primary manner of blood pressure monitoring of ELBWIs in acute phases (Fig. 2a). In 2011, when asked “what is the indication for invasive blood pressure measurement?”, 14% (14/100) of institutions selected “invasive blood pressure measurement not performed as a general rule” (Fig. 2b). In fact, “invasive blood pressure measurement” was selected more frequently in 2011 than 2006. When we assessed the “minimal target value for blood pressure,” the most frequently selected responses were “40 mmHg of systolic blood pressure” (53%, 42/80) in 2006, but were changed to “mean blood pressure in mmHg equal to gestational age in weeks” (49%, 100/49) in 2011. According to the surveys, the target blood pressure was lower in the 2011 survey compared to 2006 (Fig. 2c). In 2011, when asked about the “goal of blood pressure control,” 90% (90/100) of institutions selected “maintain urinary output,” while approximately 50% of the surveyed institutions selected “prevent the progression of acidosis” (47/100), “prevent the elevation of blood lactate level” (47/100), and “prevent cardiac pump dysfunction” (46/100).

According to the index for manner of use for cardiovascular agents, when asked “what is the indication for catecholamine use?”, 90% (72/80) of the institutions selected “poor cardiac contractility” and “hypotension” in 2006 compared to 80% (80/100) and 76% (76/100) of institutions in 2011, respectively. The response, “decreased urinary output” was selected by 78% (62/80) institutions in 2006, but decreased to 43% (43/100) institutions in 2011 (Fig. 3a). The key items in this category were designed to assess the initial usage of catecholamines. In 2006, 65% (52/80) of institutions selected “dopamine alone” and 55% (44/80) of institutions selected “a combination of dopamine and dobutamine” as the response to the question “How is catecholamine used at the start?” These responses decreased in the 2011 survey, with only 49% (49/100) and 41% (41/100) of the institutions selecting “dopamine alone” and “a combination of dopamine and dobutamine,” respectively. The dosages of catecholamines were also slightly changed between 2006 and 2011 (Fig. 3b, c). The answer “3–5 mcg/kg/min as the primary dose of dopamine” was consistently selected by approximately 60% of the institutions in both 2006 (65%, 52/80) and 2011 (58%, 58/100). The answer “10 mcg/kg/min as the maximum dose of dopamine” was the most selected dosage in both 2006 (45%, 36/80) and 2011 (66%, 66/100). Furthermore, the percentage of institutions that selected “over 10 mcg/kg/min as a maximum dose of dopamine” decreased from 43% (37/80) in 2006 to 20% (20/100) in 2011. The percentage of institutions that selected “1–3 mcg/kg/min as the primary dose of dopamine” increased from 29% (23/80) in 2006 to 41% (41/100) in 2011. On the other hand, “3–5 mcg/kg/min as the primary dose of dobutamine” was selected by 71% (57/80) in 2006 and 66% (66/100) in 2011, respectively. And the percentage of institutions that selected “1–3 mcg/kg/min as the primary dose of dobutamine” increased from 10% (8/80) in 2006 to 25% (25/100) in 2011. Although “10 mcg/kg/min as the maximum dose of dobutamine” was the most selected dosage in both 2006 (40%, 32/80) and 2011 (62%, 62/100), the percentage of institutions that selected “over 10 mcg/kg/min as the maximum dose of dobutamine” decreased from 59% (47/80) in 2006 to 31% (31/100) in 2011. For the question “what is the anticipated effect of dopamine?”, the answer “vasopressor effect” was selected by about 90% of institutions both in 2006 (86%, 69/80) and in 2011 (90%, 90/100). Additionally, “increasing renal blood flow” (90%, 72/80 in 2006 versus 75%, 75/100 in 2011), “increasing cardiac contractility” (68%, 54/80 in 2006 versus 57%, 57/100 in 2011), and “increasing bowel blood flow” (66%, 53/80 in 2006 versus 49%, 49/100 in 2011) were also selected by many institutions. On the other hand, for the question “What is the anticipated effect of dobutamine?”, the most selected answer was “increasing cardiac contractility” both in 2006 (88%, 70/80) and 2011 (90%, 90/100). The second most selected answer was “vasopressor effect” in 2006 (59%, 47/80) and 2011 (59%, 59/100).

We also surveyed the use of vasodilator agents including nitroglycerine, milrinone, olprinone, and carperitide. Nitroglycerine was used in 56% (45/80) institutions in 2006 and 47% (47/100) institutions in 2011. Milrinone was used in 34% (27/80) institutions in 2006 and 16% (16/100) institutions in 2011. Olprinone was used in 13% institutions in both years (10/80 in 2006 and 13/100 in 2011). Carperitide was used in 21% (17/80) institutions in 2006 and 9% (9/100) institutions in 2011. Additionally, in 2011 when asked, “What is the indication of vasodilator use?”, 26% (26/100) institutions selected “do not use vasodilator agents,” 51% (51/100) institutions selected “use vasodilator agents with consideration to stress-velocity relationship of left ventricle,” and 31% (31/100) institutions selected “elevation of blood pressure and decreased cardiac contractility.”

The 2011 questionnaire assessed steroid use during the acute phase. Steroids were routinely used at 5% (5/100) institutes versus selectively used at 81% (81/100) institutions. Of the 86% (86/100) institutions that indicated the use of steroids for circulatory management in acute phases, hydrocortisone was used at whole institutions, methylprednisolone was used at 1% (1/86) institution, and dexamethasone was not used at all. The most commonly used dosage of hydrocortisone was 2 mg/kg by 59% (51/86) institutions. Finally, 47% (47/100) institutions reported the prophylactic use of indomethacin for the prevention of intraventricular hemorrhaging in the 2011 survey.

4 Discussion

These surveys were conducted to investigate the actual strategy for circulatory management of ELBWIs in Japan. We understand the limitation of this study and that the responses may be biased because they are based on self-reports. Although these results do not represent actual clinical data, the questionnaires were fairly comprehensive and evaluated a variety of medical facilities.

Forty-seven institutions participated in both national surveys in 2006 and 2011 (59% of institutions in first survey and 47% of institutions in second survey). Of the three categories of institutions surveyed, there was a marked increase in the number of participating academic medical centers. In 2009, the Japanese Ministry of Education, Culture, Sports, Science and Technology issued an ordinance that stated, “National academic medical centers must have NICU in order to cultivate human resources capable of neonatal intensive care.” The increase in the number of participating institutions in 2011 is likely due to the progress in preparing NICUs at academic medical centers in Japan. It is important to note that the increased number of academic medical centers in the 2011 survey versus the 2006 survey may have impacted the overall results on this study. Because newly NICUs lack the longtime experience, they may choice the mainstream therapeutic strategy advocated in Japanese neonatal medical societies. Despite this limitation, we believe that our data highlight some key features of circulatory management strategies for ELBWIs in Japan.

In terms of indexes for circulatory management, “edema” was adopted by more institutions in 2011, as well as “heart rate,” “blood pressure,” and “urinary output” as the indexes for circulatory management in intensive care cases. “Edema” is associated with increased venous blood pressure caused by volume overload, decreased blood osmolality caused by hypoalbuminemia, and vascular hyper-permeability caused by relative steroid insufficiency, which are all common in ELBWIs. Therefore, the administration of steroids for circulatory management has recently received considerable attention and it is slowly becoming one of the more commonplace therapeutic modalities in Japan.

“Echocardiography” was selected by 95% of the institutions as a key component of examinations for circulatory management in both 2006 and 2011. Although the ratio of institutions that chose to include “blood gas analysis” and “chest X-ray” in examinations decreased from 2006 to 2011, the proportion of institutions that selected “lactate” increased. The increased monitoring of “lactate” at various institutions was likely due to the widespread use of blood gas analyzers which could measure lactate. Thus, lactate is often considered the index for tissueperfusion.

From the surveys, it is clear that echocardiography has become an essential component of neonatal examinations in Japan. This finding was likely related to relatively high penetration rate of echocardiographic machines in Japanese NICUs. This result is very similar to the increased use of“echocardiography” as the index of circulatory management in NICUs world-wide [2–14]. In 2011, Evans and colleagues reported on the global trend of neonatologists performing functional echocardiography in NICUs [2]. Neonatologists from six countries, Australia, New Zealand, France, United Kingdom, Spain, Canada, and United States, commented on the utility of echocardiography as the index for circulatory management. In 2000, 40% of all NICUs in Australia and New Zealand utilized functional echocardiography performed by neonatologists, and this percentage had increased to over 90% by 2009. Moreover, 75% of the NICUs surveyed in France had neonatologists who could perform functional echocardiography. Functional echocardiography was also performed by neonatologists in many institutions in Spain and the United Kingdom; however, the exact percentages in these regions were unclear. In the countries discussed above, high importance is placed upon uniform educational programs for neonatologists to learn functional echocardiography. In Canada, one third of tertiary NICUs have more than one neonatologist that was educated about functional echocardiography and one third of neonatologists were currently being trained.

In the United States, neonatologists only performed functional echocardiography at a few institutions. Alternatively, echocardiography was typically performed by a cardiac sonographer or a pediatric cardiologist instead. Similar to other non-specialists, neonatologists may encounter technical problems with functional echocardiography that may lead to legal or medical problems due to diagnostic error. The results of other surveys performed in Europe and in the United States revealed a large disparity in the number of institutions where echocardiography was performed— 74% in Europe and 9% in the United States [12, 13]. According to our surveys of NICUs in Japan, echocardiography for circulatory management of ELBWIs was routinely performed at 99% of institutions in 2006 and 100% of institutions in 2011. In fact in 2006, only 1% (1/80) institutions said echocardiography was not routinely performed for ELBWIs management. It is important to note that this institution was the tertiary NICU of the region, and had the capability to provide neonatal functional echocardiography if needed anytime. Based on the results of the 2011 survey, neonatologists performed functional echocardiography on ELBWIs in all institutions, and almost every institution reported that all neonatologists at the institutions could perform functional echocardiography.

The 2011 questionnaire surveyed the evaluation items of echocardiography. Interestingly, 60% of institutes used “mVcfc” and “ESWS” for the evaluation of left ventricular wall movement related to afterload, as well as other useful items for evaluating circulatory blood volume, left ventricular movement, and right ventricular pressure. Ten years prior to conducting this survey, the usefulness of evaluating ESWS-mVcfc relationship was recognized in Japan [15]. In fact, the ESWS-mVcfc relationship has become widely established as an important evaluation item to provide personalized circulatory management for each neonate. According to the review about functional echocardiography in NICUs by El-Khufash et al., evaluation of the ESWS-mVcfc relationship may be useful to assess the effect of afterload on left ventricular function [3]. It is important to note that this study did not include information regarding the clinical availability of echocardiography. Thus, there is a critical difference in circulatory management strategies between Japan and other countries.

In terms of the policy governing blood pressure control, blood pressure was monitored using invasive blood pressure measurements in 75% and 86% of the institutions included in the 2006 and 2011 surveys, respectively. In 2011, the target parameter of blood pressure was changed from systolic blood pressure to mean blood pressure, and the target minimal blood pressure at most institutions was changed from “40 mmHg of systolic blood pressure” to “mean blood pressure equal to the number of weeks of gestational age mmHg”. Dempsey et al. surveyed the diagnosis and treatment of hypotension in very low-birth-weight infants in Canadian NICUs in 2006 [4]. According to that report, 87% of institutions diagnosed infants with hypotension when the mean blood pressure dropped below the gestational age in weeks. Other institutions also used mean blood pressure as the target index, and selected other diagnostic criterion of hypotension, for example, categorized by birth weight or cut-off value at 30 mmHg. Only 26% of institutions diagnosed hypotension based solely on blood pressure, while other institutions based the diagnosis of hypotension on a host of measurements related to circulation including skin color, capillary refilling time, and urine volume added to blood pressure. Echocardiography was not discussed in these early studies because the utility of echocardiography had not yet been fully realized. In the subsequent international survey in 2012 [5], 73% of institutions diagnosed infants with hypotension when the mean blood pressure in mmHg was less than the gestational age in weeks, and 60% of institutes assessed ancillary investigation to evaluate perfusion. In those institutes, echocardiography was performed in 74%. The results of our current 2011 survey about target blood pressure were similar to the surveys mentioned before, especially the value of blood pressure that is recognized as hypotension. In the course of discussion about circulatory management of ELBWIs since 2000 in Japan, most institutions in Japan have learned and set the target value of hypotension recognized in Europe and North America.

In terms of the manner of use for cardiovascular agents, Japanese neonatologists considered hypotension and decreasing cardiac contractility as the clinical status for use catecholamine in our 2006 and 2011 surveys. The number of institutions that chose to administer dopamine alone decreased, and the initial and maximum doses of both dopamine and dobutamine also decreased. Overall, there was a tendency to use catecholamines carefully in 2011. On the other hand, vasodilator agents were already being used in many Japanese institutions in 2006. This tendency was not remarkably different in 2011, however, the percentage of institutions using each agent decreased a little (74%). Based on the questionnaire about the indication of vasodilator agent use, it was clear that echocardiography was performed to judge and estimate the administration of vasodilator agents. According to our results, nitroglycerine was the most widely used vasodilator agent. The reason for the widespread use of nitroglycerine includes reports that phosphodiesterase 3 inhibitor or atrial natriuretic peptide may dilate ductus arteriosus [16, 17]. Furthermore, steroids were administered during the acute phase in 86% of the institutions in 2011. Hydrocortisone was administered at a dose of 2 mg/kg in most institutions, which recapitulates its physiological secretion levels. However, hydrocortisone was administered at a maximum dose of 30 mg/kg in a few institutions. The large discrepancy in hydrocortisone doses may depend on the aim of use of hydrocortisone, supporting immature adrenal cortical function or treatment of shock status. Moreover, half of the institutions indicated prophylactic use of indomethacin, which is described in the Japanese guidelines regarding the treatment of patent ductus arteriosus published in 2010. According to the guidelines, prophylactic use of indomethacin is recommended to reduce the morbidity of intraventricular hemorrhage. In the aforementioned international survey [5], as the therapeutic theory of hypotension in very low-birth-weight infants, volume loading,catecholamines, and steroids were used in a variety of ways. Dopamine was most used in 80% of the institutions as first-line inotrope, alone or with dobutamine in 62% and 18%, respectively. However, there was great variation in the choice of second-line treatment, including dobutamine with dopamine (28%), dobutamine (22%), epinephrine (17%), and others. The median dose of dopamine was 5 mcg/kg/min, and the median maximum dose was 20 mcg/kg/min. The lower dose and frequency of use of dopamine in Japan compared to international use may represent the great importance that Japanese neonatologists place on cardiac contractility evaluated by echocardiography. Additionally, few reports explored the use of vasodilator agents for circulatory management of ELBWIs. The efficacy of vasodilator agents remains a divisive issue world-wide, but there is some evidence to suggest that vasodilators may improve cardiac contractility in cases of high left-ventricular afterload [15].

5 Conclusion

To the best of our knowledge, this is the first report to show the trend of circulatory management for ELBWIs in Japan. Our surveys revealed wide-spread use of echocardiography evaluations and vasodilator agents in Japan. The surveys also revealed the declining usage and dosage of catecholamines between 2006 and 2011. Taken together these results suggest that circulatory management using catecholamines, vasodilators, and other cardiovascular agents was situational and depended upon evaluation by echocardiography. Additional detailed studies are necessary to determine the advantage of these evaluations and treatment strategies on circulatory management of ELBWIs in Japan.

Disclosure statements

The authors declare no potential conflicts of interest. This article does not contain any studies with human participants or animals performed by any of the authors.