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Anthony Johnson
Anthony Johnson

NnT Lat 23 ^HOT^


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Pain is commonly experienced after surgical procedures and multiple medications (e.g., painkillers) are routinely used to control it. In February 2016, we searched for clinical trials looking at intravenous (IV) formulations (solutions that can be administered directly into a vein) of paracetamol (either IV paracetamol or IV propacetamol) and how they might manage pain after surgery.


Low quality evidence showed that IV paracetamol and IV propacetamol produced few side effects. However, patients receiving IV propacetamol complained of pain at the site their medication was infused at more often than those receiving placebo or IV paracetamol.


We included 'Summary of findings' tables as set out in the PaPaS author guide (AUREF 2012) and recommended in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 4.6.6 (Higgins 2011). The 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7) include the outcomes of pain relief, pain intensity, number of participants requiring rescue medication, opioid consumption, and number of participants with occurrences of vomiting.


We assessed the overall quality of the evidence for each outcome using the GRADE system (GRADEpro GDT 2015), and presented this in the 'Summary of findings' tables. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes.


All but nine studies administered the equivalent of 1 g paracetamol. The remaining studies administered 30 mg/kg propacetamol (Vuilleumier 1998), 10 mg/kg, 20 mg/kg or 40 mg/kg propacetamol (Hahn 2003), 15 mg/kg of IV paracetamol (Faiz 2014; Khalili 2013), 30 mg/kg of IV paracetamol (Hiller 2012), 2 g IV paracetamol (Paech 2014), a 2 g IV paracetamol arm in addition to 1 g (Juhl 2006; Salonen 2009), and a 650 mg IV paracetamol arm in addition to 1 g (Wininger 2010). In studies where there were two different paracetamol/propacetamol arms, we chose the arm administering the equivalent of 1 g of IV paracetamol for analysis.


Two studies provided analyzable data for IV paracetamol versus NSAIDs (Akarsu 2010; Koppert 2006) (130 participants). For IV propacetamol, three studies (223 participants) provided data (Farkas 1992; Hynes 2006; Zhou 2001).


Three studies with 212 participants provided data for IV paracetamol versus NSAIDs (Akarsu 2010; Akil 2014; Koppert 2006). For IV propacetamol, two studies with 143 participant provided data (Farkas 1992; Zhou 2001).


Sixteen studies provided data on categorical rating of global evaluation versus placebo, for either IV paracetamol, propacetamol, or both. Five hundred and eight participants receiving IV paracetamol evaluated therapy, 592 propacetamol, and 915 placebo. Overall, 72% (787/1100) of participants receiving IV paracetamol or propacetamol rated therapy as "good/satisfied" or better versus 58% (529/915) receiving placebo. The overall RR of IV paracetamol or propacetamol versus placebo was 1.3 (95% CI 1.3 to 1.4). The derived overall NNT for a global evaluation of "good/satisfied" or better was 6 (95% CI 4.3 to 6.7). For every six participants treated with IV paracetamol or propacetamol, one would rate their analgesia as "good/satisfied" or better who would not have done so with placebo. Based on our assessment of risk of publication bias (Table 8) these results are reliable and not subject to potential publication bias.


To assess for publication bias, we calculated the number of additional participants needed in studies with zero effect to increase the NNT for at least 50% pain relief to 10 or greater, which is what we considered to be clinically insignificant (Moore 2008). If the number of additional participants required was less than 400, we considered the result to be susceptible to publication bias. We established through these calculations that our analysis of IV propacetamol versus placebo for the number of participants with > 50% pain relief at six hours was susceptible to publication bias.


When assessing the clinical significance of the above findings, it is possible to indirectly compare the NNT for a single dose of IV paracetamol and/or IV propacetamol with that of a single dose of other analgesics (Bandolier 2010). In this update, the NNTs for combined IV paracetamol and IV propacetamol data (5 at four hours, 6 at six hours) are similar to those seen with various single doses of oral paracetamol (Toms 2008), but inferior to most orally or parenterally administered opioids. While these indirect comparisons are not surprising, the data should be interpreted with caution. The efficacy of the other analgesics in this 'league table' is measured over four to six hours, rather than discretely at four and six hours as we performed in our analyses. As demonstrated above, NNTs may increase (i.e., analgesia diminishes) if measured over six hours in drugs with a short duration of effect. Although NNTs for IV and oral paracetamol are similar, the studies included in each analysis would almost certainly have enrolled different populations. First, participants in the oral studies would have to be capable of taking oral medication immediately postoperatively. Oral administration of medications postoperatively is frequently problematic in that participants may be nauseated or vomiting or may have absorption issues, such as postoperative ileus. Second, participants in the oral studies may have had lower baseline pain. When baseline pain is low, a smaller absolute reduction in intensity is required to effect a clinically important change (Cepeda 2003).


For direct comparisons versus other analgesics, the combined analysis of IV paracetamol or propacetamol versus NSAIDs at six hours showed statistical superiority of NSAIDs. However, these data were highly susceptible to publication bias and we assessed the quality of evidence as very low according to GRADE.


When assessing the quality of findings using GRADE, we ranked quality from very low to high across the different efficacy outcomes. Lower rankings were primarily due to inconsistency (unexplained heterogeneity), imprecision (low sample sizes, low numbers of events, or wide confidence intervals), or publication bias (


We appreciated the contributions of the authors of the original review, Dr. Soledad Cepeda, Dr. Aikaterini Tzortzopoulou, Dr. Marie Belle Francia and Dr. Tamman Farhat. We are grateful to Zehui He, PhD from the Department of Big Medical Data, Guangzhou University of Chinese Medicine, Guangzhou, China, for translation and extraction of a Chinese language article. Lastly, we would like to thank Joanne Abbott, TSC, from the Cochrane Pain, Palliative and Supportive Care Group for running and compiling all of the literature searches for our review.


Cochrane Review Group funding acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane PaPaS Group. Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, National Health Service (NHS) or the Department of Health.


Non-native tree (NNT) species have been transported worldwide to create or enhance services that are fundamental for human well-being, such as timber provision, erosion control or ornamental value; yet NNTs can also produce undesired effects, such as fire proneness or pollen allergenicity. Despite the variety of effects that NNTs have on multiple ecosystem services, a global quantitative assessment of their costs and benefits is still lacking. Such information is critical for decision-making, management and sustainable exploitation of NNTs. We present here a global assessment of NNT effects on the three main categories of ecosystem services, including regulating (RES), provisioning (PES) and cultural services (CES), and on an ecosystem disservice (EDS), i.e. pollen allergenicity. By searching the scientific literature, country forestry reports, and social media, we compiled a global data set of 1683 case studies from over 125 NNT species, covering 44 countries, all continents but Antarctica, and seven biomes. Using different meta-analysis techniques, we found that, while NNTs increase most RES (e.g. climate regulation, soil erosion control, fertility and formation), they decrease PES (e.g. NNTs contribute less than native trees to global timber provision). Also, they have different effects on CES (e.g. increase aesthetic values but decrease scientific interest), and no effect on the EDS considered. NNT effects on each ecosystem (dis)service showed a strong context dependency, varying across NNT types, biomes and socio-economic conditions. For instance, some RES are increased more by NNTs able to fix atmospheric nitrogen, and when the ecosystem is located in low-latitude biomes; some CES are increased more by NNTs in less-wealthy countries or in countries with higher gross domestic products. The effects of NNTs on several ecosystem (dis)services exhibited some synergies (e.g. among soil fertility, soil formation and climate regulation or between aesthetic values and pollen allergenicity), but also trade-offs (e.g. between fire regulation and soil erosion control). Our analyses provide a quantitative understanding of the complex synergies, trade-offs and context dependencies involved for the effects of NNTs that is essential for attaining a sustained provision of ecosystem services. 041b061a72


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