A ketamine package for use in emergency cesarean delivery when no anesthetist is available: An analysis of 401 consecutive operations

Abstract Objective To evaluate the safety and effectiveness of a ketamine‐based anesthesia package to support emergency cesarean section when no anesthetist is available. Methods A prospective case‐series was conducted between December 11, 2013 and September 30, 2021 across nine sub‐county hospitals in Kenya. Non‐anesthetist healthcare providers undertook an evidence‐based five‐day training course. A structured instrument was used to collect preoperative, intraoperative, and postoperative data, and patients were contacted 6 months following the surgery to collect outcomes. The primary outcome measures were maternal and newborn survival and the ability of the ketamine package (ESM‐Ketamine) to safely support cesarean deliveries. Results A total of 401 emergency cesarean sections were performed using ketamine, administered by 54 non‐anesthetist providers. All mothers survived to discharge. Brief oxygen desaturations were recorded among 33 (8.2%) mothers, and agitation and hallucinations occurred among 13 (3.2%). There were no maternal serious adverse events. At 6‐month follow‐up, 94.2% of mothers who could be reached reported no complaints. Additionally, 402 (92.4%) of the 435 operative births survived to discharge. Conclusion The ESM‐Ketamine package can be used by trained non‐anesthetist providers to support emergency cesarean sections when no anesthetist is available. Ketamine has significant potential to increase access to emergency cesarean deliveries in resource‐limited settings.


| INTRODUC TI ON
Approximately 300 000 mothers die and many more are seriously injured from pregnancy-related causes each year worldwide. 1 While maternal mortality has significantly decreased over the past two decades, it is still unacceptably high in resource-poor settings. In 2017, high-income countries had an average maternal mortality ratio of 11 deaths per 100 000 live births, while the average for low-income countries was over 40 times greater, at 462 per 100 000 births. 1 Emergency and essential surgical care, such as cesarean delivery, is vital to reducing the burden of maternal mortality, but often remains inaccessible in resource-poor settings. 2 Although the World Health Organization (WHO) considers the ideal rate for cesarean sections to be between 10%-15%, a recent study found that the poorest quintile of countries have a mean rate of only 3.7%. 3,4 The severe shortage of anesthetists across resource limited settings has been identified as a major barrier to providing these emergency operative procedures. 5 The anesthesia workforce density is 100 times greater in high-income countries than in low-income countries, and recent surveys of referral hospitals in Africa found that only 7% have adequate anesthesia staff. 6,7 Many low-resource countries are implementing anesthetist training programs, but a 2014 systematic review found that even the most ambitious expansions would fall significantly short of meeting the global anesthesia gap in the coming decades. 5 Novel solutions are urgently needed to combat the anesthesia crisis.
Ketamine is a WHO essential medicine and has been used for over five decades to provide safe anesthesia and analgesia. It has a wide safety profile, does not depress breathing or lower blood pressure, and does not require extensive patient-monitoring equipment. 8 It is widely used to provide surgical anesthesia in conflict zones and disaster situations when no anesthetists are available, but its use in maternal care remains limited. 9 We designed, tested, and implemented a novel ketamine-based anesthesia program to address the anesthesia gap in Kenya. The 'Every Second Matters for Emergency and Essential Surgery-Ketamine' (ESM-Ketamine) package was originally designed to support emergency cesarean sections and other reproductive health operations when no anesthetist is available. Out of identified need, the ESM-Ketamine providers expanded the use cases to general surgery, orthopedic surgery, and head/neck procedures among other indications, which have been described in prior work. 10,11 In this study, we specifically examined the use of ESM-Ketamine to support emergency cesarean section when no anesthetist was available and evaluated its effectiveness and safety by analyzing maternal and newborn outcomes.

| MATERIAL S AND ME THODS
Data was collected prospectively from seven sub-county and two private hospitals in Kenya. The locations of these facilities are depicted in Figure 1, and the characteristics of these facilities are presented in Table S1. The rationale for selecting these nine study sites has been previously described. 10   According to the protocol, when the need for an emergency cesarean section was identified at a participating site, attempts were first made to contact a trained anesthetist. If no anesthesia providers were available after multiple attempts and safe transfer to another facility was not possible, the ESM-Ketamine protocol was not necessarily reflect the views of the funding partners. The funding sources had no role in the collection, analysis, or interpretation of the data nor in manuscript preparation. The mean age and weight of mothers whose cesarean sections were supported by the ESM-Ketamine package were 26.2 ± 7.5 years and 68.6 ± 10.9 kilograms, respectively ( Table 2).
All 401 mothers who received ESM-Ketamine survived their cesarean section and were discharged with no complaints ( Table 3).
There were no reported maternal serious adverse events, and none of the procedures required resuscitation or bag-valve mask ventilation of the mother. Brief oxygen desaturations (<92% for <30 s) were observed among 34 (8.5%) mothers (  Table 5, and detailed notes on each of these 23 cases are presented in Table S2. Among these 23, eight were in prolonged obstructed labor and were transferred from home or another facility that could not perform cesarean sections, eight had no fetal heart rate upon presentation for cesarean section, two had unstable fetal heart rates prior to cesarean section, two were actively hemorrhaging from abruption, four had severe intrauterine growth retardation, and one was septic. It should be noted that because the ESM-Ketamine package was never the first-choice approach, and was only employed when no anesthetist was available, the mothers had often been transferred from one, or to multiple facilities prior to receiving her emergency cesarean delivery. There was no significant difference in newborn mortality at discharge and at 6-month follow-up (P = 0.821 and 0.834, respectively) between ESM-Ketamine provider types (Table S3). All mothers survived to discharge and survived to 6-month follow-up, so there was also no difference in maternal mortality between ESM-Ketamine provider types (Table S4).

| DISCUSS ION
In a cohort of 401 mothers, we found that the use of the ESM-Ketamine package by trained non-anesthetist providers working in rural hospitals in Kenya was both safe and effective in support of emergency cesarean operations. No serious maternal adverse events were reported, and 100% of mothers along with 92.4% of the births were healthy and without complaints at discharge. Moreover, at 6-month follow-up, the incidence of complications remained low, with 5.7% of mothers reporting minor complaints. These results suggest that non-anesthetist mid-level healthcare workers trained in the use of ketamine-based anesthesia can significantly increase access to emergency cesarean delivery in resource-poor settings when no anesthetist is available. Access to cesarean section is a critical component of quality obstetric care, and immediate provision of this lifesaving procedure is vital to reducing maternal mortality and disability. However, shortages of trained anesthetists, a lack of essential equipment, and poor infrastructure make administration of modern anesthesia in lowresource settings extremely challenging. 2 Ketamine is a general anesthetic available worldwide and is a promising solution to enable cesarean delivery when no anesthetist is available.

TA B L E 2 Demographic characteristics of mothers who received the ESM-Ketamine package for emergency cesarean delivery
Ketamine has been used as an anesthetic agent since the 1960s, and has numerous characteristics making it ideal for safe use in field settings. 12 It is administered intravenously or intramuscularly, has minimal effects on central respiratory drive, produces bronchodilation, and unlike other anesthetics, does not depress the cardiovascular system.  This study did have a few limitations. It was conducted in one country (Kenya), and the majority of cases were treated at a single center (Sagam Sub-County Hospital). However, the nine study sites do represent a broad range of contexts and included severely resource constrained facilities in settings of extreme poverty (refugee and nomadic), sub-county community hospitals, and large county referral hospitals.
These nine facilities are located in counties that have the highest burden of maternal mortality in Kenya. 17 Furthermore, it should be noted that only 73.3% of mothers could be reached at 6-month follow-up.
Many of the women belong to nomadic tribes or do not own phones, and as a result could not be contacted. Additionally, due to the prospective case series design of the study, comparisons between the efficacy of ketamine and standard general anesthesia could not be made.
Over the course of the past 7 years, the Kenyan Health system has been severely impacted by multiple prolonged healthcare worker strikes. 18 These strikes resulted in significant reductions in hospital admissions and considerable health worker migration both within the country and out of the country. As a result, many trained ESM-Ketamine providers were unable to utilize their skills, because the hospital they found themselves employed in could not support cesarean deliveries and other operative procedures.
In summary, this study provides evidence that use of the ESM-Ketamine package by non-anesthetist mid-level providers in support of emergency cesarean sections may be safe and substantiates the immense promise of ketamine to increase access to lifesaving cesarean delivery in resource-limited settings when no anesthetist is available.
We acknowledge that anesthesia is best provided by specialty-trained anesthetists who have access to necessary medicines, infrastructure support, and equipment, and the long-term goal is to have skilled anesthetists available globally. However, this is not the current reality, and training many thousands of anesthetists will take decades while hundreds of thousands of mothers in resource-poor settings suffer. The alternative to emergency cesarean surgery is often death and is particularly devastating as two lives are lost. It is immoral to deny mothers access to emergency anesthesia and life-sustaining surgery simply because optimal anesthesia services are not available.
Ketamine and other systems-level innovations can play a major role in reducing maternal morbidity for underserved populations globally.

ACK N OWLED G EM ENTS
The authors thank Debora Rogo, Javan Jamba, Wenslaus Adenya, Juddy Odhiambo, and Jacktone Juma from the African Institute for Health Transformation at Sagam Community Hospital (Kenya) and Moytrayee Guha, Alicia Lightbourne, and Lori Garg from the MGH Global Health Innovations Laboratory for their tireless efforts in making this work possible over the years.

CO N FLI C T S O F I NTE R E S T
The authors have no conflicts of interest.