Recipes for obstetric spinal hypotension: the clinical context counts.
Context is king--the importance of the clinical environment
Why is it necessary to distinguish between differing clinical contexts? There are marked differences in the availability of staff, equipment, drugs and infrastructure across different levels of the health sector. This is tacitly acknowledged by the reluctance to implement some research findings in resource-poor environments. Management strategies need to be adapted to match available clinical skill, drug availability, monitoring capabilities and patient profile. To frame further discussion, we propose a classification of three contexts that potentially require different clinical approaches (Table 1).
Resource-poor clinical contexts are limited on multiple fronts. For example, poorer staffing ratios are compounded by a lack of expertise and training. The responsible doctor does not necessarily have an understanding of the principles of anaesthesia, and the job is often allocated by default to the doctor or nurse who is unable to perform the surgery. This is further complicated by a lack of available equipment (such as electrocardiographic monitoring) and inconsistent drug supplies. Vasopressor choice is often dictated by availability rather than preference. In addition, the attending doctor is frequently required to perform more than one function, often as both obstetrician and anaesthetist, and will be making rapid assessments of patients in multiple locations in the lead-up to surgery. This increases the likelihood of missing significant obstetric and medical comorbidities and significant dehydration in patients presenting to theatre. Attending doctors may need to administer the initial anaesthetic and also conduct the surgery, being required to monitor the anaesthetic either directly while operating or via a nurse. This scenario applied in 7% of the anaesthetic deaths analysed in a recent national report.  The anaesthetist may have very limited experience of general anaesthesia for caesarean section (CS) and therefore inappropriately administer spinal anaesthesia in cases where general anaesthesia is indicated. Management strategies must therefore be tailored to a low-expertise environment with poorly prepared patients and a lack of anaesthetic vigilance. Theoretically, simple preventive strategies such as fixed, low-dose vasopressor infusions may minimise the need for rapid clinician intervention and therefore hold an advantage over strategies highly reliant on clinician intervention.
The SA context
The SA health system includes hospitals from all three contexts. Tertiary hospitals are often well staffed and well equipped, while district-level hospitals, especially in the rural setting, suffer from staffing and equipment deficiencies. Even at regional level, the number of CSs performed outstrips the number of trained anaesthesia providers, creating a relatively resource-constrained environment.  In the Saving Mothers report for 2011-2013,  three out of every four mothers who died as a result of direct anaesthetic causes received spinal anaesthesia, with 'small district hospitals contributing disproportionately to anaesthetic related maternal deaths'. This pattern is unusual, as mortality rates generally tend to increase in more specialised centres owing to greater case complexity. In SA this pattern is reversed, with 56% of all deaths occurring in district hospitals, 35% in the regional centres and 8% in the tertiary centres.  The majority of women who died in district-level hospitals received a spinal anaesthetic. This pattern has been noted in previous reports,  where 64% of all spinal deaths were related to severe uncorrected hypotension. Although the exact case fatality rate for spinal v. general anaesthesia is unknown because denominator data are incomplete, the total number of anaesthetic deaths in SA is increasing, particularly in the group who receive spinal anaesthesia.  This represents an area where relatively simple interventions may result in significant changes.
The clinical context and current obstetric evidence
Research on obstetric spinal hypotension has largely been performed under highly standardised research conditions, which do not reflect the broader SA context. There is an intense focus on management of patients by senior clinicians, usually in elective rather than emergency cases and often incorporating highly specialised invasive monitoring. This is a requirement for high-quality research, where sophisticated methods elucidate an underlying mechanism and are then translated into simple clinical interventions. However, given that these interventions will be applied in a significantly different context, they must still be tested in the real-world setting. While SA has continued to produce internationally recognised research, a gap exists between the research context and the reality of the SA public health sector. There is a need to translate critical research into pragmatic management strategies that target a specific clinical context, and then test these strategies in that environment.
Relevant current literature
Over the past 10 years, significant progress has been made in defining and predicting hypotension, and describing haemodynamic changes during spinal anaesthesia for CS. These insights have all contributed to the development of the current state-of-the-art recipe. We will discuss each of these aspects in turn, focusing on clinical context gaps.
Incidence and definition
The incidence of obstetric spinal hypotension varies according to the definition applied.  Klohr et al.  found across 63 publications that the incidence of spinal hypotension was 27% when defined as a systolic blood pressure (SBP) <70% of baseline, but that it increased to 39% using an SBP of <75% of baseline. Up to 80% of spinal anaesthetics in obstetrics require the use of a vasopressor to treat hypotension.  Most of these studies came from resource-rich environments, and there are few studies that look at this incidence in resource-constrained environments. It is reasonable to assume that the incidence and severity of hypotension could be significantly higher in the latter setting. This is important because the NCCEMD process does not address the 'near-misses', and therefore does not quantify the true extent of the problem.
Prediction of obstetric spinal hypotension
Avoiding spinal hypotension is important for maternal and fetal safety as well as for maternal comfort, since even minor degrees of hypotension are associated with an increased incidence of intraoperative nausea and vomiting.  The prediction of obstetric spinal hypotension has received considerable attention and has recently been the subject of review in a local journal.  While a number of practical predictors such as body mass index, maternal age and baseline heart rate have shown potential, results have been conflicting and applied predominantly to elective patients. Autonomic indices such as heart rate variability have also shown promise,  but have yet to be translated into a practical clinical tool. Given the high incidence of hypotension, [1,9] research in this area should focus on predicting which patients will have severe hypotension, where outcomes relating to maternal and fetal safety are more likely to be affected. We need simple clinical parameters that identify high-risk patients and can be coupled to preventive strategies or earlier referral to specialist centres. There are no scoring systems in daily use addressing this need.
Haemodynamic changes under spinal anaesthesia
The dominant mechanism behind obstetric spinal hypotension is a reduction in arterial sympathetic tone, [2,3,13,14] although venodilatation probably also plays a role. This hypotension results in an increased heart rate,  although a small proportion of patients may respond with hypotension and bradycardia.  Better understanding of the mechanism of hypotension has led to clinical management moving from a fluid-based strategy towards a vasopressor-based prophylactic strategy supported by fluid co-loading.  One study proposed that heart rate may be 'the best surrogate indicator of cardiac output during spinal anesthesia for cesarean delivery'.  This is of particular relevance to the resource-poor setting, where targeting simple surrogate outcomes such as heart rate could be explored for practical implementation in clinical guidelines.
The choice of vasopressor
In recent years there has been a move towards using phenylephrine as the agent of choice in treating obstetric spinal hypotension.  Despite prevailing evidence, practice has been slow to change even in settings with similar resources to those in which the research was conducted.  In an excellent editorial, Smiley  questioned the reluctance of anaesthetists to embrace the use of phenylephrine and offered several explanations for this. One reason put forward was that the choice is not perceived as 'being quite a life and death issue'. This argument could be advanced in resource-rich settings where a dedicated anaesthetist is available to respond quickly and appropriately to a decrease in blood pressure, but it may not apply to a less ideal context. Experienced anaesthetists potentially respond more rapidly to signals such as patient symptoms and heart rate, but this cannot be relied upon in settings where there is no dedicated anaesthetist. Preventive strategies that reduce the need for rapid intervention should have important advantages in this context. Prophylactic strategies have not been adopted in SA because of concerns about feasibility in resource-constrained hospitals and about safety in the hands of inexperienced clinical staff, a concern echoed in international guidelines.  This concern may be unfounded, given that simple strategies such as fixed-rate, low-dose phenylephrine infusions have a low complication rate and provide improved haemodynamic stability and are therefore particularly suited to the inexperienced anaesthetist. Also, it is only by effective prophylactic use of vasopressors that maternal symptoms due to spinal hypotension can be prevented.
Vasopressor management strategies
Modern strategies for combating obstetric spinal hypotension employ a combination of fluid and a vasopressor. The recommended first-line agent is phenylephrine,  with the notable exceptions being the patient who responds to spinal anaesthesia with bradycardia and hypotension, or has undiagnosed cardiac disease and unexpectedly requires positive inotropy. Recent literature has moved the debate from the choice between ephedrine and phenylephrine to the manner in which phenylephrine should be given. This reflects an acceptance of phenylephrine as the drug of choice. Initial work using high phenylephrine infusion rates (100 [micro]g/min) and aggressive fluid co-loading showed that hypotension could be almost eliminated, but at the cost of reactive hypertension. [10,19] Subsequent work with lower-dose phenylephrine infusions supported prophylactic infusions as part of routine CS.  Further dose-finding studies suggested that a range of 25-50 [micro]g/min seemed to give the most benefit with the fewest side-effects. [20,21] Haemodynamic studies also suggested that targeting the baseline heart rate may be the best way to maintain cardiac output during phenylephrine administration. 
A recent systematic review concluded that prophylactic phenylephrine infusions reduced maternal hypotension, nausea and vomiting without altering other relevant maternal or neonatal outcomes.  The setting of this work is elective CS in healthy patients, in ideal clinical conditions. In a recent editorial, Butwick et al.  noted that the potential impact of phenylephrine infusions in a number of higher-risk groups, including women undergoing unplanned CS, has not been well elucidated. They went on to state that 'titrated phenylephrine infusions co-administered with crystalloid should now be recommended for prophylaxis against spinal hypotension'.  However, because the context of the research is very specific, it is not clear how to implement this in differing environments.
Strategies to combat hypotension on a pharmacological basis can be divided into 'reactive' or 'preventive' approaches. Reactive approaches generally involve early and aggressive treatment with fluid and a vasopressor bolus in response to a significant decrease in blood pressure. Implicit in these strategies is a vigilant anaesthetist with adequate experience in the field. Many guidelines offer the choice of ephedrine or phenylephrine as the vasopressor, including the National Institute for Health and Care Excellence (NICE)  and SA guidelines.  These recommendations reflect caution in applying conclusions drawn from research on elective CS in healthy women to the urgent CS in women with comorbidity in different clinical environments.
The NICE clinical guidelines for CS  state that 'Women who are having a CS under regional anaesthesia should be offered intravenous ephedrine or phenylephrine, and volume pre-loading with crystalloid or colloid to reduce the risk of hypotension occurring during CS.' They further recommend that 'intravenous ephedrine or phenylephrine should be used in the management of hypotension during CS'. One guideline in the UK recommends that anaesthetists should 'only consider phenylephrine infusion for elective CS and if they have received training in equipment and the technique'. For emergency cases, a bolus technique is recommended.  2004 SA recommendations  state that 'the standard first line and very safe vasopressor is ephedrine', although later Essential Steps in the Management of Obstetric Emergencies (ESMOE) informal recommendations allow for either ephedrine or phenylephrine to be used. No mention is made of prophylactic vasopressor infusions. It is evident that despite overwhelming evidence for the benefit of prophylactic phenylephrine infusions in elective patients, clinicians are reluctant to implement these findings even in the resource-rich setting in which the research was performed. This was highlighted more than 6 years ago, but continues to be a concern. 
Closing the gap
It is clear that there is a gap between the research clinical context and the application of research to the resource-poor context. In order to close this gap, we need to develop and test models in a broader context and acknowledge the need for context-sensitive management strategies. Table 2 offers some hypothetical context-sensitive guidelines and the rationale for these approaches.
These recipes need to be refined and tested with pragmatic studies that evaluate the ability of institutions in differing contexts to achieve success with differing guidelines in resource-limited areas, by conducting well-designed, multicentre studies. In SA this could be accomplished through the establishment of an obstetric anaesthesia research group focused on large pragmatic clinical trials aimed at improving maternal safety during CS. Such a network could be established rapidly by making use of existing structures such as the South African Obstetric Anaesthesia Special Interest Society, the ESMOE and the South African Perioperative Research Group. This network should set national priorities for obstetric anaesthesia research and focus on the SA context. Research centres could be established in resource-limited areas, where potential interventions could be tested in small pilot trials preceding large national pragmatic trials. A proposed research agenda for such a programme is outlined in Table 3.
In recent years there have been significant advances in the field of obstetric anaesthesia. High-quality research has outlined the mechanism, described the haemodynamic changes and refined the management of obstetric spinal hypotension. However, there is a gap between this knowledge base and its implementation in real-world settings outside the research environment. We need to acknowledge this gap, and focus on contextualising research findings in a pragmatic fashion. This is best achieved through innovative, collaborative research, starting in academic centres, and applying the findings in the context of limited-resource environments.
[1.] Klohr S, Roth R, Hofmann T, Rossaint R, Heesen M. Definitions of hypotension after spinal anaesthesia for caesarean section: Literature search and application to parturients. Acta Anaesthesiol Scand 2010;56(7):909-921. DOI:10.1m/j.1399-6576.2010.02239.x
[2.] Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009;111(4):753-765. DOI:10.1097/ALN.0b013e3181b437e0
[3.] Langesaeter E, Dyer RA. Maternal haemodynamic changes during spinal anaesthesia for caesarean section. Curr Opin Anaesthesiol 2011;24(3):242-248. DOI:10.1097/ALN.0b013e31818a401f
[4.] Dyer RA, Biccard BM. Ephedrine for spinal hypotension during elective caesarean section: The final nail in the coffin? Acta Anaesthesiol Scand 2012;56(7):807-809. DOI:10.1m/j.1399-6576.2012.02719.x
[5.] Macarthur A. Solving the problem of spinal-induced hypotension in obstetric anesthesia. Can J Anaesth 2002;49(6):536-539. DOI:10.1007/BF03017377
[6.] Pattinson RC, ed. Saving Mothers 2011-2013: The Sixth Report of the National Committee for Confidential Enquiries into Maternal Deaths in South Africa. Pretoria: Government Printer, 2014.
[7.] Reed A, Mumba JM, Dyer R. A spotlight on obstetric anesthesia in the developing world: Finally getting the attention it deserves. Anesth Analg 2015;120(6):1179-1181. DOI:10.1213/ANE.0000000000000722
[8.] Rout CC, Farina Z. Anaesthesia-related maternal deaths in South Africa: Chapter Seven of the 5th Saving Mothers Report 2008-2010. South Afr J Anaesth Analg 2012;18(6):281-301. DOI:10.1080/22 201173.2012.10872868
[9.] Rout CC, Rocke DA. Prevention of hypotension following spinal-anesthesia for cesarean-section. Int Anesthesiol Clin 1994;32(2):117-135. DOI:10.1097/00004311-199400000-00010
[10.] Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section. Br J Anaesth 2004;92(4):469-474. DOI:10.1093/bja/aeh088
[11.] Bishop DG. Predicting spinal hypotension during caesarean section. South Afr J Anaesth Analg 2014;20(4):170-173. DOI:10.1080/22201181.2015.959336
[12.] Chamchad D, Arkoosh VA, Horrow JC. Using heart rate variability to stratify risk of obstetric patients undergoing spinal anesthesia. Anesth Analg 2004;99(6): 1818-1821. DOI:10.1213/01.ANE. 0000140953.40059.E6
[13.] Sharwood-Smith G, Drummond GB. Hypotension in obstetric spinal anaesthesia: A lesson from pre-eclampsia. Br J Anaesth 2009;102(3):291-294. DOI:10.1093/bja/aep003
[14.] Langesaeter E, Rosseland LA, Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: A randomized, double-blind comparison of low-dose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion. Anesthesiology 2008;109(5):856-863. DOI:10.1097/ALN.0b013e31818a401f
[15.] Kinsella SM, Lohmann G. Supine hypotensive syndrome. Obstet Gynecol 1994;83(5):774-788.
[16.] Butwick AJ, Columb MO, Carvalho B. Preventing spinal hypotension during caesarean delivery: What is the latest? Br J Anaesth 2015;114(2):183-186. DOI:10.1093/bja/aeu267
[17.] Smiley RM. Burden ofproof. Anesthesiology 2006;111(3):470-472. DOI:10.1097/ALN.0b013e3181b16466
[18.] Mayer J, Jackson G. Hypotension Management in Obstetric Regional Anaesthesia. Reading, UK: Royal Berkshire Trust, 2015.
[19.] Ngan Kee WD, Khaw KS, Ng FF. Prevention of hypotension during spinal anesthesia for cesarean delivery: An effective technique using combination phenylephrine infusion and crystalloid cohydration. Anesthesiology 2005;103(4):744-750.
[20.] Allen TK, George RB, White WD, Muir HA, Habib AS. A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery. Anesth Analg 2010;111(5):1221-1229. DOI:10.1213/ANE.0b013e3181e1db21
[21.] Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg 2010;111(5):12301237. DOI:10.1213/ANE.0b013e3181f2eae1
[22.] Heesen M, Kolhr S, Rossaint R, Straube S. Prophylactic phenylephrine for caesarean section under spinal anaesthesia: Systematic review and meta-analysis. Anaesthesia 2014;69(2):143-165. DOI:10.1111/anae.12445
[23.] National Institute for Health and Care Excellence (NICE). Caesarean section. NICE guidelines [CG132]. Published November 2011, last updated August 2012. https://www.nice.org.uk/guidance/ cg132 (accessed 25 July 2016).
[24.] Dyer RA, Rout CC, Kruger AM, van der Vyver M, Lamacraft G, James MF. Prevention and treatment of cardiovascular instability during spinal anaesthesia for caesarean section. S Afr Med J 2004;94(5):367-372.
Accepted 11 April 2016.
D G Bishop, (1) MB ChB, FCA; R N Rodseth, (2) MB ChB, FCA, MMed, Cert Crit Care, MSc, PhD; R A Dyer, (3) MB ChB, FCA, PhD
(1) Perioperative Research Group, Department of Anaesthetics, Edendale Hospital, Pietermaritzburg, South Africa, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa
(2) Perioperative Research Group, Department of Anaesthetics, Grey's Hospital, Pietermaritzburg, South Africa, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa; and Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio, USA
(3) Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Corresponding author: D G Bishop (firstname.lastname@example.org)
Table 1. Suggested definitions of clinical context in obstetric anaesthesia Clinical context Personnel Equipment Resource rich Dedicated senior Invasive monitoring, anaesthetist with full anaesthetic obstetric expertise facilities and infusion pumps Resource Dedicated junior Basic monitoring constrained anaesthetist, lacks (NIBP/ECG/Sp[O.sub.2]) experience, slower in all cases, reaction times anaesthesia machine, infusion pumps usually available Resource poor Part-timer/nurse, lack NIBP, Sp[O.sub.2] in of experience, slower most cases, Ambu bag and reaction times, divided oxygen available. No attention infusion pumps. Inconsistent drug and sundry supply Clinical context Health system Resource rich Well-assessed and triaged, hydrated and optimised patients. Modern theatres, recovery facilities and good staffing ratios Resource Intermittent-level care--may be dehydrated constrained patients, unrecognised comorbidity. Overloaded systems with delays in accessing theatres Resource poor Not reliably assessed and managed preoperatively. Undetected pathology more likely. Poor theatre design and no recovery facility NIBP = non-invasive blood pressure; ECG = electrocardiogram; Sp[O.sub.2] = peripheral capillary oxygen saturation. Table 2. Suggested vasopressor recipes based on clinical context Context Presumption Fluids Resource Patients hydrated and well Co-load rich assessed, vigilant senior anaesthetist Resource May be fluid deficit, Consider preload, constrained unrecognised pathology, administer junior anaesthetist co-load Resource May be fluid deficit and Preload/ poor unrecognised pathology, junior rehydrate and anaesthetist, divided attention co-load Context Vasopressor Notes Resource Phenylephrine infusion Good evidence-based rich (start at 50 [micro]g/ research Target min), titrate to effect near-normal baseline heart rate and blood pressure Resource Phenylephrine infusion Applied from constrained (25 [micro]g/min) Titrate research-setting data if experienced, otherwise Good theoretical basis, run at fixed rate: bolus requires testing in intermittently and real-world setting discontinue if reactive hypertension Resource Phenylephrine (500 Lack of evidence for this poor [micro]g) or ephedrine approach Requires study (50 mg) in first litre of prior to application crystalloid--run freely then convert to bolus strategy Table 3. Proposed perioperative research agenda for obstetric spinal hypotension Need Rationale Validate traditional predictors Early identification of of spinal hypotension in context high-risk patients a priority, and continue to explore novel enabling appropriate resource predictors with practical allocation via referral and applicability Develop a robust scoring system potentially different management to identify mothers at risk of strategies hypotension following spinal anaesthesia for CS, using these predictors Develop easily available novel scoring tools (such as the obstetrics shock index) Comparison of a prophylactic Safe practical ways to utilise vasopressor infusion with a the current knowledge base in treatment bolus strategy for the resource-poor settings should be management of hypotension tested following spinal anaesthesia for CS Develop simple methods of applying prophylactic vasopressor infusion strategies in resource-poor environments Research the principle of Newer techniques first studied targeting heart rate for the in controlled, strictly prevention and treatment of protocol-driven studies before hypotension: initially in the testing in other contexts academic setting, and then apply to regional centres Develop an obstetric research Co-ordinating research will network in SA and agree on a enable bigger, multicentre research framework and pathway trials, while drawing on experience from established centres
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|Title Annotation:||CLINICAL UPDATE|
|Author:||Bishop, D.G.; Rodseth, R.N.; Dyer, R.A.|
|Publication:||South African Medical Journal|
|Date:||Sep 1, 2016|
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