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作者：Deborah Brauser  
出處：WebMD醫學新聞

January 22, 2010 (邁阿密海灘) — 根據發表於重症照護醫學會第39屆重症照護研討會的一篇新世代研究結果，在心臟手術前後給予新生兒的鎮靜劑與止痛劑，與不良神經發展結果如心智、動作與字彙發展延遲無關。
　　
　　這項榮獲研討會年度科學獎之一的研究，是由第一作者、西加拿大綜合小兒治療計畫追蹤小組、Stollery 兒童醫院、亞伯達大學小兒科臨床助理教授Gonzalo Garcia Guerra醫師發表。
　　
　　根據發表內容，雖然動物研究顯示止痛藥對於腦部發育有害，但還不清楚這些結果是否可推論於人類新生兒。
　　
　　共同研究者、西加拿大研究計畫成員、Stollery 兒童醫院、亞伯達大學小兒科臨床副教授、Ari Joffe醫師向Medscape Critical Care表示，許多現有的資料顯示，前述的關聯僅適用於早產嬰兒，就我們所知，這是首篇檢視進行心臟手術的足月新生兒有無此關聯的研究。
　　
　　【沒有藥物與不佳結果有關】
　　為了進行本研究，研究者回顧評估在2003年4月至2006年12月接受心臟手術且存活的95名新生兒的資料。
　　
　　Joffe醫師解釋，我們回顧檢視在這段期間內，每名新生兒所接受的所有鴉片類藥物、苯二氮平類(benzodiazepines) 藥物、k他命與水化氯醛(chloral hydrate) ，且加入我們的資料庫，接著，校正心臟手術時的各種因素，如心臟病灶、術前與術後的疾病嚴重度、手術期間的因素等，看使用這些藥物是否與2歲時的發育結果有關。
　　
　　其他評估的變項包括，住院期間使用的劑量以及使用藥物的天數，神經發育結果之測量：適應行為評量系統(ABAS)一般適性複合分數、ABAS動作類分數、貝萊嬰兒發展量表(BSID)測量心智與動作延遲(分數<70)以及BSID詞彙發展延遲(分數<第15百分位)。
　　
　　結果顯示，給予的鎮靜和止痛劑中，不論是累積劑量或每日劑量，都與病患的任何不佳的神經發育結果無關。
　　
　　Joffe醫師表示，我們認為這些結果是可靠的，但是我不認為令人感到驚訝，動物模式比較適合於早產者，我們的病患都是足月新生兒，我們的研究並未提及早產兒，但是，至少在這些孩童來說，這些發現是可靠的，當然，理想的話，應進行後續研究來確認這些結果。
　　
　　他指出，在這些狀況中，實際上不太可能不用這些藥，這些都是重症嬰兒，沒有人會想要阻礙鎮靜劑與止痛藥物的使用，所以，我們的研究發現並未指出要改變實務。
　　
　　他報告指出，研究者計畫繼續追蹤該研究的這些孩童，我們目前著眼於兩年的結果，隨著孩童長大，我們計畫探討5歲時的神經發展結果，以確保沒有更長期的影響。
　　
　　【令人振奮的結果】
　　重症照護研討會共同主席、會議共同主持人、紐約市康乃爾大學Weill醫學院小兒重症照護醫療小組主任、小兒科臨床教授Bruce Greenwald醫師表示，我認為，作者們辨別使用鎮靜劑與止痛劑對於這類病患的長期發育結果有無影響是很有趣的研究。
　　
　　未參與該研究的Greenwald醫師表示，對我和SCCM的聽眾們而言，這是令人振奮的，瞭解到我們例行性使用的這些藥物是安全的，沒有任何的負面後遺症，事實上，這會造成許多小兒科專責主治醫師的實務改變，如果他們本來認為這些藥物與長期發育問題有關的話。
　　
　　Greenwald醫師表示，我們希望，如果有明確的長期負面關聯，提出給美國食品藥物管理局的報告與證據力將會使大眾有所警覺，有趣的是，就我所知，這是第一個直接地回答這個問題的研究。
　　
　　他指出，雖然該研究的樣本數屬於合理的範圍，如果有更大型的研究，那麼結果將更有用也更具說服力，不過，這是一個有難度的研究，特別是新生兒—要在進行這類手術之後追蹤他們數年，所以，如果當時可以進行更大型的研究就更好了，總之，這是個好的開始。
　　
　　Greenwald醫師表示，發表時有人提出一些更有趣的問題，例如作者們是否有探討體外循環的期間或深度低溫的期間，這些都是這類病患在手術室中可能會使用的，事實上，他們有許多資料因為發表時間限制而未說明，我認為，有許多人急切地等待文獻出版，詳述在此未能報告的細節，我自己也期待能早日拜讀。
　　
　　Alberta Health and Wellness資助本追蹤研究的登記。Joffe醫師與Greenwald醫師皆宣告沒有相關財務關係。
　　
　　重症照護醫學會(SCCM)第39屆重症照護研討會：摘要25。發表於2010年1月10日。


Sedatives, Analgesics Not Linked to Adverse Neurodevelopment in Neonates After Cardiac Surgery

By Deborah Brauser
Medscape Medical News

January 22, 2010 (Miami Beach, Florida) — Sedatives and analgesics given to neonates right before and after cardiac surgery are not associated with adverse neurodevelopmental outcomes, such as mental, motor, and vocabulary delays, according to the results of a new cohort study presented here at the Society of Critical Care Medicine (SCCM) 39th Critical Care Congress.

The study, which received one of the Congress' Annual Scientific Awards, was presented by first author Gonzalo Garcia Guerra, MD, assistant clinical professor in the Department of Pediatrics at the University of Alberta, Stollery Children's Hospital in Edmonton, and part of the Western Canadian Complex Pediatric Therapies Project Follow-Up Group.

According to the presentation, "although animal models have suggested detrimental effects of anesthetic drugs on the developing brain, it's been unclear whether those results could be extrapolated to human neonates."

"A lot of the current data suggest that that association would apply only to preterm babies," co-investigator Ari Joffe, MD, associate clinical professor of pediatrics at the University of Alberta/Stollery Children's Hospital and fellow member of the Western Canadian research collaborative, told Medscape Critical Care. "To our knowledge, this is the first study to examine this relationship in full-term neonates having cardiac surgery."

No Drugs Associated With Adverse Outcomes

For this study, the investigators retrospectively evaluated data from 95 neonates who underwent open heart surgery between April 2003 and December 2006 and survived.

"We looked back during this time at all the opioids, benzodiazepines, ketamine, and chloral hydrates received by each neonate, and added that to our database," explained Dr. Joffe. "We then adjusted for various factors, such as heart lesion, preoperative and postoperative severity of illness, and intraoperative factors, during the cardiac surgery to see if there was an association between these drug exposures and developmental outcome at 2 years of age."

Other variables evaluated include dose during hospitalization and number of days the drug was given. Neurodevelopmental outcome measures included the Adaptive Behavior Assessment System (ABAS) General Adaptive Composite score, the ABAS motor subscore, Bayley Scale of Infant Development (BSID) measures of mental and motor delay (score <70), and the BSID vocabulary delay (score <15th percentile).

Results showed that none of the drugs given for sedation and analgesia, in terms of their cumulative amount or daily dose, were associated with any adverse neurodevelopmental outcomes in the patients.

"We thought these results were reassuring, but I don't think they were really surprising," said Dr. Joffe. "The animal models are probably more equivalent to humans who are preterm, and our patients were all term neonates. Our study does not address preterm babies, but at least in these children, the findings are reassuring. Of course, ideally, these results should be confirmed by further studies."

He noted that it would be "virtually impossible not to give these drugs in these situations. These babies are critically ill and no one would want to hold back sedation and analgesia drugs. So it's a relief to see that in our findings there's no indication to change practice."

He reported that the investigators plan to continue following up with the children from the study. "We were looking at 2-year outcomes. As the children get older, we plan to look at their 5-year neurodevelopmental outcomes to make sure there's nothing more subtle there."

Heartening Results

"I thought it was of great interest that the authors were able to discern whether or not the use of sedatives and analgesics in this patient population had an impact on their long-term development," said session comoderator Bruce Greenwald, MD, FCCM, FAAP, professor of clinical pediatrics and chief of the Division of Pediatric Critical Care Medicine at Cornell University Weill Medical College in New York City, and Critical Care Congress cochair.

"It was heartening for me and the [SCCM] audience to learn that these drugs that we use regularly appear to be safe and that the authors were unable to find any negative consequences of their use. In fact, it would cause a great change in many of the practices of pediatric intensivists if they had found that these drugs are associated with long-term developmental problems," said Dr. Greenwald, who was not involved with the study.

"One would hope that if there was a consistent long-term negative association, reports to the [US Food and Drug Administration] and the weight of the evidence would alert the public," added Dr. Greenwald. "Interestingly, this was the first study that I know of that was directly geared toward answering this question."

He noted that although the study was of reasonable size, the results would be more useful and convincing if the study had been larger. "However, this is a difficult study to do, especially in neonates — to follow them for several years after this type of surgery. So although it would be wonderful if a larger study could be done at some point, this is a nice beginning."

Dr. Greenwald said that some of the more interesting questions that came up during the presentation included whether the authors looked at the duration of cardiopulmonary bypass or the duration of deep hypothermia that might have been used in the operating room on these patients. "In fact, they have a whole lot of data that they did not present because of the time constraints of the presentation format. I think many anxiously await the publication of an article that details some the aspects of the study not reported here. I look forward to reading that myself."

The registry from this follow-up study was funded by Alberta Health and Wellness. Dr. Joffe and Dr. Greenwald have disclosed no relevant financial relationships.

Society of Critical Care Medicine (SCCM) 39th Critical Care Congress: Abstract?25. Presented January?10, 2010.