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Snakebite is a neglected tropical disease that leads to more than 120,000 deaths every year. In 2019, World Health Organization (WHO) launched a strategy to decrease its global burden by 2030. There is a range of issues around different interventions for the management of snakebite. Decisions around these interventions should be informed by evidence from systematic reviews (SR).
An overview of SRs was conducted by searching 12 electronic databases, PROSPERO, contacting experts and screening the bibliography of included reviews. Screening, data extraction, and quality assessment (through AMSTAR-2) was done by at least two overview authors independently with discrepancies sorted by consensus. A narrative synthesis was conducted.
Principle findings
The overview found 13 completed SRs that has looked at various aspects of management of snakebite envenomation. There was one SR on first aid, nine on effectiveness and safety of snake anti-venom (SAV), two on drugs to prevent adverse reactions due to SAV therapy, and one on surgical interventions for management of snakebite envenomation. All, except one, SR was appraised to have critically low confidence as per AMSTAR-2 Criteria. Evidence base was restricted to few studies for most interventions.
High quality evidence from SRs is required to inform guidelines and health system decisions which can bring down the burden of snakebite. The review indicates the need to fund high-quality SRs, evidence gaps and core outcome sets which can inform guideline recommendations, funding priorities for conduct of future trials. Variation in species distribution as well as intra-species variation in venom composition implies the need for conduct of region or, nation or state (sub-national) specific randomised controlled trials and SRs on different SAVs and their dosing regimens.
Author summary
Snakebite is a neglected tropical disease which has received priority attention in the global health space with WHO setting a target to decrease death and disability due to snakebite to 50% by 2030. High quality systematic reviews can inform policy and practice. We searched 13 electronic databases and PROSPERO, screened reference lists, and contacted experts. We identified 13 completed systematic reviews which has reviewed effectiveness and safety for first-aid, snake anti-venoms, drugs to prevent adverse reactions and fasciotomy. Evidence for interventions often came from few studies. We judged confidence on the results of the systematic reviews using AMSTAR-2 and all except one review was judged to have critically low confidence. Evidence with respect to specific geographic settings and for many specific anti-venoms is unavailable at the synthesis level and at the primary study level. Evidence related to late adverse reactions, wound-related outcomes, quality of life, duration of hospitalisation, cost, and disability is scarcely reported. Funding evidence gap maps, systematic reviews and development of core-outcome sets based on the results of this overview and subsequent conduct of randomised controlled trials for snakebite envenomation is essential.
Citation: Bhaumik S, Beri D, Lassi ZS, Jagnoor J (2020) Interventions for the management of snakebite envenoming: An overview of systematic reviews. PLoS Negl Trop Dis 14(10): e0008727. https://doi.org/10.1371/journal.pntd.0008727
Editor: Ana M. Moura-da-Silva, Instituto Butantan, BRAZIL
Received: June 9, 2020; Accepted: August 17, 2020; Published: October 13, 2020
Copyright: © 2020 Bhaumik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data underlying the results presented in the study is available as appendices for the study.
Funding: The study is supported by an internal LMIC seed grant to SB from The George Institute for Global Health. (https://www.georgeinstitute.org/) SB is supported by the University International Postgraduate Award (UIPA) by University of New South Wales (UNSW), Sydney, Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared no competing interests exist.
Snakebite is a neglected tropical disease which leads to more than 120,000 global deaths every year [1]. Disability, social and economic costs of snakebite is not well studied but overall burden of snakebite is understood to be grossly underestimated [2]. Snakebite is global in nature but it mostly affects rural and tribal communities in South Asia, Southeast Asia, and Africa [2]. A modelling study has estimated that inadequate provision of quality healthcare for snakebite affects 146.7 million people adversely [3].
Although 5.4 million snakebites occur annually, only about half of them leads to envenoming (the clinical condition after bite from a venomous snake). Snake venoms are highly complex and diverse, which show inter-species as well as intra-species variation [4–7]. Consequently, snakebite envenomation represents myriad clinical manifestations. These include, but not limited to, local wound, neurotoxic, renal, musculoskeletal, cardiovascular, haemostatic and mental health related manifestations [2, 4]. Management of snake envenomation involves first aid, management of local and systemic effects followed by management of complications and follow-up for addressing any sequalae or disability [4]. Snake anti-venom (SAV) is the only specific intervention that is required, but SAVs are of various types and there is substantial debate on not only its dosage and frequency but also, in its design and suitability in different geographic regions and for different species.
In 2019, the World Health Organization (WHO) has released a comprehensive strategy which aims to decrease the burden of death and disability due to snake envenomation by 50% before 2030 [8]. Ensuring safe and effective treatment is one of the four key pillars which WHO has identified. We have previously analysed existing WHO guidelines for management of snakebites and found poor methodological rigour in its development [9]. The WHO Guidelines were not based on systematic search, appraisal, and grading of evidence. Using evidence from high-quality systematic reviews (SRs) is crucial for decision-making. An overview of SRs will not only serve as a "single window front-end" on the current evidence but will also help identify gaps at the evidence synthesis level of interventions for management of snakebite envenomation. An overview of SRs is a relatively new approach for evidence synthesis with research methodology and guidance around it evolving [10]. It essentially involves systematically searching, appraising, and synthesising the results of related and relevant SRs on a single topic to support decision making by clinicians, policy makers, and guideline developers.
Methods and analyses
The protocol for the overview was registered prospectively in PROSPERO (CRD42018073048). The PRISMA checklist is provided in S1 Table.
Justification of overview of systematic reviews as the right approach for the study
We followed the Cochrane's Comparing Multiple Interventions Methods Group Editorial Decision Tree to establish whether our review would better fit an overview design or an intervention SR design, with or without a network meta-analysis [11]. The overview of SRs is an appropriate study design for our research topic because we did not intend to compare multiple interventions to draw inferences about the comparative effectiveness of the interventions but intended to summarise the available evidence on different interventions for management of snakebite envenoming.
Criteria for considering reviews for inclusion
We included studies which met the following criteria:
- ○. Study Design: SR, irrespective of the design of the individual studies included by them, irrespective of whether they have conducted a meta-analysis or not.
- ○. Population: SRs that have included studies with patients being treated for snakebite envenoming (irrespective of the snake species and irrespective of the age and sex of the participants or the setting).
- ○. Interventions: SRs that have included any kind of medical, surgical or complementary or alternative therapies that can be used as a single intervention or concurrently with others, irrespective of the comparator.
- ○. Primary Outcomes
- All-cause mortality.
- Any specific type of mortality (including but not limited to death due to neuromuscular paralyses or coagulopathy or cardiovascular shock, acute kidney injury).
- Early adverse reaction (immediate or anaphylactic reaction and/or early anaphylactoid reaction (archetypal use)- as defined by systematic review authors).
- Late adverse reactions to snake anti-venoms or serum sickness (as defined by the systematic review authors).
- Major Complications including but not limited to major haemorrhage, paralysis, muscle loss or kidney failure after snakebite (as defined by the systematic review authors).
- The proportion of wounds that have healed/are infection free or validated cosmetic outcome scores for wounds.
- Mental health-related outcomes (as defined by the systematic review authors).
- ○. Secondary Outcomes
- Duration of hospitalization
- Quality of life
- Any cost-related outcome
- Any other wound-related outcome (including but not limited to necrosis)
- Death or disability as composite outcome (as defined by systematic review authors)
- ○. If there was an update, we included only the latest version.
- ○. We included SRs irrespective of language or date of publication
Search methods for identification of reviews
Electronic database.
We searched Ovid MEDLINE(R), Global Health, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database, APA PsycInfo, CINAHL by EBSCO-Host, and the Campbell Library. We also conducted supplementary search on Scielo (https://www.scielo.org/) for additional coverage of potential Spanish and Portuguese literature from Latin America. Detailed search strategy for all databases (updated 16th May 2020) including the supplementary Search on Scielo (updated 04th August 2020) is provided in S1 Text.
Selection of reviews
In the first phase, two authors (SB and DB OR ZL) independently screened the studies retrieved based on titles and/or abstracts and marked each record as "exclude" or "needs full text for evaluation". Full texts of all studies marked as "needs full text for evaluation" by either of the two authors were obtained and reviewed independently by two authors for consideration of inclusion based on criteria discussed above. Disagreements were resolved by consensus.
Data extraction and management
Two authors (SB and DB or ZL) independently extracted data. We did not contact the authors of SRs, or authors of individual studies, for any clarification or missing data. Disagreements were resolved by consensus between two authors (SB and DB or ZL). We extracted data using a pre-designed data extraction sheet.
Data synthesis
We narratively synthesised the results of the SRs. No additional quantitative analyses (additional indirect comparisons or network meta-analyses) or critical appraisal of studies included in SRs were conducted.
We provide a narrative description of the summary results from the included SRs. When there was an overlap between two SRs (i.e. had included same studies), we abstracted both the results, compared and contrasted them and reported both. If meta-analysis was conducted, the summary statistics is abstracted and reported, but in absence of meta-analysis, we present the summary results of the included studies. Unless otherwise mentioned all values correspond to 95% confidence interval (CI). We grouped studies for synthesis based on intervention types.
Assessment of methodological quality of included SRs
Quality assessment for included SRs was done independently by two authors (SB and DB or ZL) using the AMSTAR– 2 [12] criteria and discrepancy, if any, was resolved by consensus. AMSTAR-2 is an internationally accepted tool for assessment of quality of SR. The AMSTAR-2 assessment pertains to the conduct of SR and is independent of the quality of included primary studies.
The assessment of quality of included primary studies, if reported in included SRs is presented.
Difference between protocol and actual conduct of overview
As a matter of transparency, we note some protocol deviations during the conduct of the overview. Death or disability as composite outcome and any other wound-related outcome were not a priori outcomes noted in the protocol. These were added to capture additional evidence reported in SRs which could be useful for decision making. We searched 13 electronic databases, much more than originally planned. We had originally planned to search TOXLINE which is no longer a separate subset and relevant records subsumed within PubMed.
Search results
We retrieved 76 records from search in electronic databases, 28 records in PROSPERO and two by citation screening in the original search. We removed duplicates (n = 30) and after screening following titles and abstracts (56 articles excluded) we retrieved 20 full texts from the original search strategy. For the supplementary search for Latin American literature, we retrieved 38 records with no duplicates and after screening, assessed four full texts.
Overall, we evaluated 24 full texts and finally included 13 completed SRs [13–25]. We identified three ongoing SRs which have protocol available in PROSPERO or are published [26–28] which meet our inclusion criteria.
Fig 1 shows the PRISMA flowchart documenting the process. Reasons for exclusion at full-text phase are mentioned in S2 Table.
Description of included systematic reviews
The three ongoing SRs study effectiveness of SAV on neuromuscular paralysis [26], interventions for managing thrombotic microangiopathy due to snakebite [27], and the role of therapeutic plasma exchange in acute care (with a planned subgroup analysis for snakebite) [28].
We found 13 completed SRs. Characteristics of included SRs are summarised in Table 1.
The SRs we found looked at the following aspects of management of snakebite envenomation:
- First-aid for snakebite: One SR looked comprehensively at all first-aid interventions for management of snakebites that is feasible for laypeople without medical background [21]. The SR had included 14 studies, of which two were randomised controlled trials (RCT), five were non-randomised intervention studies with control group, four were retrospective cohort studies, and three were prospective cohort design.
- Effectiveness and safety of SAVs: Six SRs evaluated different types of SAV for envenoming taking a snake species or genus specific approach [14, 16, 17, 19, 24, 25], while three took a more broad non-species-specific approach [20, 22, 23].
The SRs which took a snake-species specific approach included 81 studies of various designs. Among the studies which took a non-species-specific approach one was an empty review [23], while the other two SRs included 31 studies in total [20, 22].
- Interventions to prevent adverse reactions due to SAV therapy: Two SRs looked at interventions for preventing adverse drug reactions due to SAV therapy [13, 15]. Together, these two SRs included nine studies.
- Other interventions for management of snakebite envenomation: There was only one SR which evaluated surgical interventions for North American Crotaline snake envenomation [18]. It included 42 studies but did not report the total number of participants.
Synthesis of findings from included systematic reviews on interventions
A narrative overview of the findings from the included SRs is presented in a structured manner based on typology of interventions.
First-aid for snakebite.
The SR on first-aid [21] had a broad scope and included six different types of interventions. It included 1295 participants from 14 studies which were conducted in Australia (n = 4), Brazil (n = 2), India (n = 2), Myanmar (n = 2), Nigeria (n = 2), USA (n = 1) and China (n = 1).
- Tourniquet
The SR identified seven studies on effect of tourniquet on snakebite and found:
- ○. No significant differences between those treated with a tourniquet (with or without additional incisions in the bite wound) and victims who received no tourniquet or no first aid for death (Relative Risk (RR) 0.77; 95% CI 0.13 to 4.41); and the occurrence of death or disability (Odds Ratio (OR) 4.7; 95% CI 0.58 to 212).
- ○. No significant difference was seen between those treated with a tourniquet (irrespective of additional wound incisions),in comparison to those patients with snakebite who received no tourniquet or no first aid for the following outcomes: acute renal failure (RR 1.24; 95% CI 0.33 to 4.66) [22], acute respiratory failure (RR 1.4; 95% CI 0.3 to 6.53) [22], occurrence of haemorrhagic syndrome (RR 0.95; 95% CI 0.77 to 1.17) [30], and incidence of multiple organ dysfunction syndrome (RR 1.85; 95% CI 0.56 to 6.15).
- ○. Only a single study included in this SR had studied duration of hospitalisation and found no significant difference in the duration of hospital stay between snakebite victims treated with a tourniquet and those receiving no first aid (MD -0.3 days; 95% CI -1.9 to 1.3), another found a significant increase in the duration of hospital stay between snakebite victims treated with a tourniquet and those receiving no first aid (4.6±2.0 days vs 3.7±2.5 days; MD 0.9, p = 0.04).
- ○. Mixed evidence on wound related outcomes from different studies was found:
- ■. Increase in local swelling for those treated with a tourniquet (and no local incisions) (RR 1.71; 95% CI 1.49 to 1.96) and those treated with a tourniquet and wound incisions (RR 1.71; 95% CI 1.49 to 1.96), when compared to snakebite victims receiving no first aid.
- ■. Significantly increased odds for an increased severity of local envenomation in snakebite victims receiving a tourniquet, compared to those not receiving a tourniquet (OR 4.31; 95% CI 1.33 to 13.89).
- ■. No significant differences were found between snakebite victims treated with a tourniquet (with or without additional incisions in the bite wound) and victims who received no tourniquet or no first aid for tissue necrosis (RR 0.75; 95% CI 0.14 to 4.12) and local oedema (RR 0.98; 95% CI 0.6 to 1.61).
- Incision of the bite wound
The SR identified two studies on effect of incision of the bite wound and found:
- ○. No statistically significant difference in the incidence of death or disability (OR 4.3; 95% CI 0.18 to 275) between those whose bite wounds were incised as a part of first-aid and those receiving no first aid.
- ○. No difference in occurrence of haemorrhagic syndrome (RR 1.05; 95% CI 0.71 to 1.53), in comparison to those receiving no first aid.
- ○. Significantly increased incidence of local swelling upon incision (RR 1.66; 95% CI 1.40 to 1.97), in comparison to those receiving no first aid.
- ○. Significant decrease in the duration of hospitalisation in those whose snakebite wound was incised in comparison to those whose bite wound was not incised (2.9±1.6 days vs 4.6±2.2 days; MD -1.70 days; p = 0.03)
- Suction of the bite wound
The SR identified only one study which looked the effect of suction of bite-would and reported:
- ○. No significant increase in the occurrence of death or disability (RR 1.33; 95% CI 0.07 to 26.98) compared to patients who had not received first aid.
- ○. No significant increase in the duration of hospitalisation (median 6 days vs. 4 days, p = 0.7) compared to those who did not receive suction.
- Snake stones
The SR identified two studies on effect of snake stones (animal bones or stones used in folk and indigenous medicine for treatment of snakebite) and found:
- ○. No difference in the occurrence of death or disability between those treated with snake stones in comparison to those receiving no first aid (OR 13; 95% CI 0.39 to 823).
- ○. No significant decrease in duration of hospitalisation in those with snakebite patients who had applied snake stones in comparison to those not receiving any first-aid (MD -0.2; 95% CI -2.57 to 2.17) or in comparison to those not being treated by snake stones (median 2.5 days vs. 4 days; p = 0.09).
- Traditional medicine and concoctions:
The SR identified two studies that evaluated the use of traditional medicine and concoctions and found:
- ○. Statistically significant increased odds for death or disability in snakebite patients treated with concoctions applied to the bite wound, compared to those who had not applied concoctions to the wound (OR 15; 95% CI 1.4 to 708).
- ○. Statistically significant increase in odds for death or disability in snakebite patients who had ingested concoctions (6/10), compared to those who did not ingest (OR 20; 95% CI 1.4 to 963).
- ○. No significant decrease in the duration of hospitalisation in those who received traditional medicine, compared to those who did not received no first aid (MD 0.6 days; 95% CI -1.23 to 2.43). There was no difference in the duration of hospitalisation between those who were treated with concoctions applied to the bite wound, in comparison with those on whom no concoction was applied (median 5days vs. 4 days; p = 0.6), those who ingested concoctions, in comparison to those who did not ingest (median about 4 days in both; p = 0.84).
- Pressure Immobilization
The SR identified seven studies related to pressure immobilisation on snakebite but none of them reported any outcome of our interest.
Effectiveness and safety of SAVs: species or genus specific systematic reviews.
Four SRs looked at evidence with respect to Crotalidae polyvalent immune Fab antivenom (FabAV) for Crotalinae sp (North American Pit Viper) envenomation. One looked specifically at children [24], one on those with severe envenomation [19], one on those who developed medically significant late bleeding [14] and another looked specifically at safety aspects [17]. This apart, two other SR looked at Echis occelatus envenomation in West Africa and Vipera spp envenomation in Europe [29, 30]. The evidence with these regards is summarised below:
- ○. Crotalidae polyvalent immune fab (FabAV) in children
The SR found 10 studies (six case reports, three descriptive reports, and one RCT) with a total of 47 children [24]. When pooled the prevalence of adverse events was found to be in 8.5% of the children (4/47). Of these, three were acute reactions, and one was serum sickness on hospital discharge. All except two studies did not have any recurrent local effects (defined as progression of local injury after initial response to SAV) and late coagulopathy (defined as coagulopathy occurring after initial normal values). One study had 8% (1/12) recurrent local effects and 8% (1/12) late coagulopathy while another study had 75% (3/4) patients who had late coagulopathy.
- ○. FabAV in those with severe envenomation
The SR found 19 studies consisting of 24 people with severe North American Pit Viper envenomation[19]. Seven cases were described in five cohort studies and 17 cases were described in 14 single patient case reports or non-cohort case series. Persistent severe venom effect (limb swelling, limb pain, soft tissue bleeding, thrombocytopenia, neurotoxicity, or compartment syndrome) was seen in 0% of patients in cohort study but 53% of patients in non-cohort reports. No patient developed systemic bleeding but recurrent and/or delayed-onset severe defibrination syndrome was found in patients.
- ○. FabAV in those who develop medically significant late bleeding
The SR included 19 cohort studies (two cohorts were within the context of RCTs) consisting of 1017 patients. Late bleeding was seen in nine patients (0.9%; 95% CI 0.4% to 2.2%) with five patients developing medically significant late bleeding. (0.5%; 95% CI 0.1% to 1.7%) [14]. Eight of the nine patients who had late bleeding were cases of Rattlesnake envenomation. No deaths or sequalae of any kind was reported.
- ○. Safety of FabAV for North American crotaline snake envenomation
The SR included 11 studies (seven retrospective studies, three prospective studies, and one that had both prospective and retrospective data) and included 661 participants [17]. The combined estimate of incidence of early hypersensitivity was 0.08 (95% CI 0.05 to 0.11). The pooled estimate of serum sickness incidence was 0.13 (95% CI 0.07 to 0.21) from amongst the seven studies which reported it.
- ○. SAV for carpet viper (Echis ocellatus) envenoming in West Africa
The SR found 22 studies (four RCTs, 12 observational studies, and six preclinical studies) [16]. Pooled meta-analysis found that the odds of dying decreased by as much as 75% (OR 0.25; 95% CI 0.14 to 0.45) of dying among those treated with a specific antivenom compared to non-specific or no anti-venoms. Mortality rates were more than double when there was stock-out of reliable SAVs (RR 2.33; 95% CI 1.26 to 4.06).
- ○. Anti-European Vipera spp antivenoms
The SR found 40 studies (excepting pre-clinical studies which were included) on various types of anti-European Vipera spp antivenoms involving about 2602 participants [25]. There were 14 studies each on Zagreb (n = 1306), and on ViperaTAb (n = 197), 11 studies on ViperFAV (n = 558), three studies on Biomed (n = 43), two studies on Bulbio antivenom (n = 69), and one case-report on Viekvin (n = 1). There were eight studies in the SR which did not specify the antivenom used.
Deaths were reported only in patients given Zagreb SAV and the rate was 0.2% (n = 5). The median length of hospitalisation in patients who were given ViperFAV or ViperaTAb was significantly less than those being given IM Bulbio or Zagreb antivenoms (1 to 4.8 days versus 2 to 18 days).
Adverse reactions were reported in 1.5% (37 of 2408 cases including 7 cases of anaphylaxis) 5%) in which SAV was administered. This varied between 0.5 to 2.0% in patients administered with ViperaTAb, Zagreb, and ViperFAV antivenom, 4.7% in those who received Biomed antivenom. No adverse reactions were reported in those administered Bulbio antivenom (n = 67) and in the single patient administered Viekvin antivenom.
Effectiveness and safety of SAVs: broad non -species/genus specific systematic reviews.
There were three SRs which took a broad non-species / genus specific approach and investigated the role of SAVs in venom induced consumption coagulopathy in people with snakebite envenomation [23], effectiveness and safety of SAVs available commercially in sub-Saharan Africa [22], and, on different dosing regiments (low vs. high) of SAVs [20].
- SAVs for managing venom induced consumption coagulopathy
The SR on RCTs on this issue did not find any studies which met eligibility criteria [23].
- SAVs available in sub-Saharan Africa
The SR [22] took a phased approach, wherein the authors first conducted a market analysis to obtain a comprehensive list of SAVs available in the sub-Saharan Africa and then looked systematically for evidence (of any design) for these SAVs specific to the region. This is crucial because there is substantial intra-species variation based on climate and geography. The SR found 26 studies (two RCTs, five non-randomised comparative clinical studies, 11 observational cohort studies, and eight anecdotal clinical reports) on nine SAVs available in the sub-Saharan Africa.
The SR did not find any studies from sub-Saharan Africa on the following seven SAVs, although they were available in the markets:
- ○. ASNA antivenom–D (Bharat Serums and Vaccines)
- ○. Snake Venom Antiserum (PanAfrica) aka Premium-A (Premium Serums)
- ○. Snake Venom Antiserum (Central Africa) aka Premium-CA (Premium Serums)
- ○. Afriven 10, Snake Venom Antiserum (African) aka VINS-A (VINS Bioproducts)
- ○. Anti-Snake Venom Serum Central Africa aka VINS-CA (VINS Bioproducts)
- ○. Snake venom antiserum Echis ocellatus (VINS Bioproducts)
- ○. SAIMR-Boomslang (SAVP)
- ○. EchiTabPlus (ICP) and EchiTabG (Micropharm)–One RCT and two observational studies were found related to EchiTabPlus and EchiTabG for Echis ocellatus envenoming. For the RCT, exact difference in outcomes were not presented though the SR mentioned "ET-Plus was found to be a little more effective than an initial dose of one vial of EchiTabG, and a little less safe"[22]. Very low case-fatality was reported in the two observational studies from Nigeria and Central African Republic on use of EchiTabPlus or EchiTabG for Echis ocellatus envenoming. However, an early hypersensitivity reaction was seen in 21 patients (6.9%).
- ○. Inoserp-Pan African (Inosan)- The SR found two studies which found case fatality rates of 3.17% in Senegal and 4% and 0.92% in northern Benin and Guinea from a multicentre observational study with 8% of patients in whom adverse events were reported. The multi-country study from Benin and Guinea had many cases of Echis ocellatus in Benin. No specific species information was presented in the SR for the study from Senegal. Blood coagulability was found to be restored within 24 hours in 87.5% and 98% of patients in the respective studies.
- ○. Fav-Afrique aka FAV-A(Sanofi Pasteur)- FAV-A was studied in eight cohort studies from Cameroon (2/41 had minor adverse event; no death, no serum sickness), Ghana (mortality rate 1.8%), Chad (mortality rate 6.67%), Central African Republic (mortality rate 7.47% in a prospective study and 0.5% in a retrospective study), and Republic of Djibouti (no deaths or adverse events reported in three cohorts). The study in Cameroon and Central African Republic were conducted in an area where Echis ocellatus was common. The three cohorts from Djibuouti found FAV-A to restore blood coagulability on Echis pyramidum bites too. Only one patient in a single study from Djibouti which enrolled 31 patients had necrosis. No information about necrosis was reported in the SR for other studies.
- ○. SAIMR-Polyvalent (SAVP)—There were six studies on SAIMR-Poly in which a total of 5 deaths were seen in 144 included patients (death rate 3.47%). The SR noted varying rates of adverse events with one showing severe early (anaphylactoid) reaction in 76.47% patients. The adverse event rate across studies was between 10% to 15%.
- ○. SAIMR Echis ocellatus / Echis Pyramidum (SAVP)—There were three studies from Nigeria, of which one was an RCT. None of the three studies reported any deaths. The RCT in the SR found that SAIMR-Echis was more effective than SAIME Behringwerke in terms of reversing haematological abnormalities more rapidly (data not specifically reported). The RCT also noted early hypersensitivity in four out of 23 patients while one observational study found adverse reaction in 14 out of 48 patients (one study did not report adverse effects).
- ○. Antivipmyn-Africa (Instituto Bioclon /Silanes)–The SR found four studies which reported case fatality rates of 3.11% in Benin, 10% in Central Africa, 18.2% in Guinea, and 15.4% (low dose) and 17.6% (high dose) in another study in Guinea. A low rate of adverse events (between 10% to 15%) was reported across studies on Antivip-A.
- ○. ASNA antivenom—C (Bharat Serums and Vaccines)—There was one post-marketing surveillance study from Central Ghana which found 22% mortality and 7.58% anaphylactic shock. Another study included in the SR was from Nigeria and it reported that ASNA-C was ineffective in restoring blood coagulopathy and causing in allergic reactions in many cases. All the studies were conducted in areas where Echis Occelatus bites are common.
- ○. Vacsera POLY- One retrospective study from Ethiopia reported 17% deaths among 23 patients with prolonged clotting time who were treated with Vacsera Poly.
Different dosing regimens of SAVs.
The SR [20] found five RCTs on low versus high dosage regiments of SAV, out of which four were from India and one from Brazil. However, the distinction used between low and high dosage was not specified a priori and as a consequent there were overlaps with low doses ranging from 20–220 ml while high dosage ranged from 40–550 ml. A volume-based classification of dosing regimens as done in this SR might also be inappropriate, because different antivenoms have different protein concentrations leading to differences in the amount of protein administered for the same volume[31].
Four trials reported mortality out of which one did not report any death. Pooled result from other three trails showed no significant difference in death between those with high and low doses of SAVs. (RR 0.69; 95% CI 0.38 to 1.26)
There was no significant difference in rates for neurological complications (RR 0.82; 95% CI 0.23 to 2.94), acute renal failure (RR 0.87; 95% CI 0.62 to 1.21), and bleeding or disseminate intravascular coagulation (RR 0.77; 95% CI 0.46 to 1.29). No significant difference was noted in time to normalisation of clotting time between high dose versus low dose group in one trial (10hours 23 minutes versus 9 hours) while another trial found a significant difference (20.67 ± 9.61 hours in high dose group (regimen I), 16.55 ± 9.84 hours in low dose (regimen II), and 13.4 ± 7.16 hours in low dose (regimen III)).
Adverse SAV reactions (itching, urticaria, and erythema) occurred in eight of 30 patients in the high dose group and 8 out of 60 patients in the low dose group in one trial. The other three trials did not report any major adverse events.
Duration of hospitalisation was reported from two studies and results were pooled to find that low-dose SAV led to 1.27 less days of hospitalisation compared to the high dose group (MD −1.27 days, −2.05 to − 0.5). Another study also reported duration of hospitalisation, but the SR could not pool the data due to non-reporting of standard deviation. It found "no difference in the average hospital stay (days) between the low dose and high dose (8.42 vs. 9.02 days).
The study calculated cost-effectiveness using prices of Indian polyvalent SAV prices. It stated that a low-dose regimen led to savings of INR 500–2000 (USD 10–140) excluding any other expenditures (including expenditure on hospitalisation, and other therapies).
Interventions to prevent adverse reactions due to SAV therapy.
Two SR investigated interventions to prevent adverse reactions to SAV administration [13, 15]. The study published earlier [13] included only two RCTs from Brazil and Sri Lanka while Habib 2011 [15] included three RCTs and four cohort studies. The SRs found:
- Prophylactic medication to prevent early adverse reaction (EAR)
The seven studies that Habib et al [15] included had 10 comparisons of adrenaline alone or in combination, hydrocortisone alone, anti-histamine alone or in combination with steroids. The overall pooled RR for any prophylactic pre-medication to no pre-medication for EAR was 0.70 (0.50 to 0.99) but there was high heterogeneity implying different effects of particular types of pre-medications.
- Prophylactic Adrenaline
Nuchpayoon et al [13] included only one trial from Sri Lanka which found that those who received adrenaline had significantly lesser adverse allergic reactions to SAV (Haffkine poly-specific) overall (RR 0.25; 95% CI 0.11 to 0.57) than those receiving placebo. The trial had also noted that severe reactions were many times more in the placebo group over the adrenaline group (RR 0.10; 95% CI 0.01 to 1.77). No death was recorded in either of the groups. No patient developed hypertension (blood pressure >160/100 mmHg), arrhythmia (other than sinus tachycardia), or neurological deficits suggestive of cerebrovascular accidents in either of the groups.
Habib 2011 [15] had included three studies (including the Sri-Lankan trial which was included in Nuchprayoon) on adrenaline-containing pre-medication (adrenaline alone or with promethazine/hydrocortisone) and found a risk-ratio of 0.32 (95% CI 0.18 to 0.58) with no heterogeneity, when compared to no pre-medication or placebo. The other two studies were a retrospective cohort from Papua New Guinea and nested cohort from Australia with risk-ratio of 0.27 (0.10, 0.79) and 0.78 (0.21, 2.90) respectively for subcutaneous adrenaline-containing pre-medication compared to no pre-medication.
- Prophylactic Steroid
While Nuchprayoon did not find any studies which had looked at the role of steroid alone, Habib found one RCT from Sri Lanka which found no difference for development of EAR between use of hydrocortisone and placebo (RR 0.98; 95% CI 0.70 to 1.39) and the trial was prematurely stopped [15].
- Prophylactic Anti-Histamine
Both SRs found one trial from Brazil on Bothrops envenomation patients to prevent reactions due to Bothrop specific SAV (three manufactures: Instituto Butantan, Fundaçao Ezequiel Dias, or Instituto Vital Brazil) and found no difference in acute reactions between those who received promethazine and those who did not (RR 0.98; 95% CI 0.50 to 1.93). One patient from each treatment group suffered severe anaphylaxis. No death was reported in either of the groups.
- Prophylactic Steroid along with anti-histamine
Habib [15]found five studies which had explored several combinations of prophylactic steroid with different anti-histamine and although separate pooled RR for this was not reported, it mentioned that the result was not statistically significant and there were issues with heterogeneity, paucity and quality of data.
Other interventions for management of snakebite envenomation.
There was only one SR under this category which was done in the context of consensus-based recommendations being developed for surgical consideration for North American Pit Viper (Crotalinae) envenomation [18]. It found evidence on several key issues, one of which pertained to diagnostic accuracy issues and hence not of interest (diagnostic criteria for compartment syndrome) to this overview:
- Early excision of tissue near bite in Crotaline spp. envenomation
The SR found two old observational studies (with no comparison group) when early excision along with tourniquet and ice-water immersion but not SAV being administered typically showed worse tissue outcomes (not exactly specified). In the modern context, where SAV administration is the norm, the review found no comparative clinical trials which had examined role of early excision (alone or as an adjunct with SAV). It however, found 16 studies which showed excellent results (outcomes were not explicitly stated) with SAV without incisions or excisions in comparison to just one study which found to the contrary. The SR found no literature in relation to debridement of necrotic tissue or in relation to management of puncture wounds on tendon sheaths for patients with snake envenomation.
- Prophylactic fasciotomy for preventing compartmental syndrome in Crotaline spp envenomation
Prophylactic fasciotomy (done before compartment syndrome develops in Crotaline spp) alone or in combination with standard therapy including SAV was found to not improve outcomes. The outcomes were not explicitly specified but are related to "scarring and wound-healing" and "elevated compartment pressure". The quality of evidence was determined to be moderate by the consensus group and was based on two human and one porcine study.
- Therapeutic Fasciotomy for treating compartmental syndrome in Crotaline spp envenomation
It was found that FAb SAV administration decreased myonecrosis and decreased the need for fasciotomy. Therapeutic fasciotomy in those with diagnosed compartmental syndrome for Crotaline spp envenomation was found to not decrease intra-compartmental pressure as per a recent evidence-based review included in the SR. However, despite this, the consensus committee mentioned about a "large body of evidence supporting fasciotomy in compartment syndrome caused by fractures, crush injuries, and electrical burns, it is logical that fasciotomy should be performed in cases where aggressive antivenom therapy fails to correct impaired tissue perfusion." The evidence was not cited, while a recommendation was made for therapeutic fasciotomy through an algorithm developed by the consensus panel.
Quality of primary studies included in systematic reviews
Seven included SRs did not conduct any quality appraisal of included studies [14, 18, 19, 22, 24, 25, 30]. The study on low-dose versus high dose of SAV reported that they used the Cochrane tool and reported that the included trials were of "moderate quality" [20]. The study to understand safety of FabAV [17] used the Jadad scale for RCTs, Newcastle-Ottawa Quality Assessment Scale for observational prospective studies, and a chart review tool for retrospective studies. The Jadad score for the included RCT had an Endorsement Frequency of 84.5%, all the prospective cohort studies had a score of 7 out of 9 (9 being lowest risk of bias) while the retrospective studies had varying quality.
Quality of evidence on different outcomes were reported to be measured by GRADE approach in only two SRs [20, 21] and in both the SRs. the quality of outcomes was found to be low or very low.
Confidence in results of included SRs
We used AMSTAR-2 for assessing the confidence in results of included SRs and found that except for one [23], all were rated to have critically low confidence in results. This implies the SR had more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available primary studies on the topic. We rated Maduwage et al. [23] to have high overall confidence in the results of the SR. AMSTAR-2 ratings for the included SRs are summarised in Fig 2.
Summary of main results
The available evidence from 13 completed SRs related to management of snakebite envenomation covers a range of interventions (pharmacological and otherwise) and in diverse settings (geographical, species specific, and otherwise). While effect estimates vary, it is evident that there are glaring gaps in terms of availability and quality of evidence. We have summarised the summary evidence for all the interventions at synthesis level in Table 2. Largely we see that high-quality review-level evidence is not available for almost all intervention-outcome pairs. There is no synthesised evidence with regards to quality of life or mental health outcomes across the board and only few SRs [20, 25, 32] had envisaged to understand the effect of interventions to decrease health systems burden (through cost or duration of hospitalisation).
We found that evidence for several key aspects regarding first aid for snakebite envenomation is required. Evidence pertains to only a few studies and with small number of participants [32]. Low quality evidence exists that tourniquet, incision, suction, snake stones and traditional medicines and concoctions are not effective for several outcomes, although evidence on several key outcomes is not available or show no difference compared to their non-application for first aid. There is no evidence on pressure immobilisation related to outcomes of interest.
Evidence with respect to specific geographic settings and for many specific anti-venoms is unavailable at the synthesis level and also at the primary study level (as for example in Africa [22]). Despite SAV being the only life-saving intervention for snakebite dosing regimens and their safety and effectiveness, key clinical issues are studied only in a handful of trials–the evidence base thus being low quality, inconclusive and not providing contextual information [20, 33]. Evidence related to late adverse reactions, wound-related outcomes, quality of life, duration of hospitalisation, costs and disability is scarcely available. Prophylactic medications for preventing adverse reactions for SAV has been studied in only a few RCTs and there is some evidence on the effectiveness and safety of adrenaline for this purpose [13, 15]. There is no evidence suggesting the use of steroids, anti-histamines or their combination for preventing adverse reactions. The SRs on species-specific treatment issues (including SAVs and role of surgical interventions) are mostly restricted to North American Pit Viper (Crotalidae) and Carpet Viper (Echis occelatus) envenomation [14, 18, 24, 34, 35]. The FabAV antivenom is found to be effective in many studies for children, for those with severe envenomation and for those who develop medically significant late bleeding). It has been found to be safe in several studies. Specific SAV for Carpet Viper envenoming in West Africa is more effective in decreasing mortality compared to non-specific SAVs or no SAVs. There is no synthesised evidence pertaining to envenomation due to other snake species specifically.
Overall completeness and applicability of evidence
All except one SR were rated to have critically low-quality using AMSTAR-2 –this is a major cause of concern for evidence synthesis for snakebite. The only high quality review was an empty review [23], implying high confidence that there is no evidence for effectiveness and safety of SAV for neuromuscular paralysis. Key critical issues in the included SRs were lack of prior registration and/or publication of protocol, non-provision of list of excluded studies at full-text level, and non-usage of appropriate risk of bias tools and/or its usage to interpret results and discussion.
Most SRs did not assess the quality of included primary studies. Critical appraisal of included primary studies is a standard component of systematic reviews as it helps assess the quality of evidence. It enables decision makers to understand the level of confidence one might have in the results of the primary study. Even reviews which used risk of bias tools for critical appraisal of tools did not appropriately report the use of the tools, and the use of risk of bias/GRADE for drawing conclusions were not appropriate. Potet et al. [22] had planned to use the Newcastle Ottawa Scale to assess quality but abandoned their plan citing that the tool was "not well adapted to the overall very low quality of selected studies" and instead used a study-design based criterion. The Newcastle Ottawa Scale is, in fact, designed to assess quality of non-randomised studies. Several design aspects, beyond study design such as validity of measurements and blinding of outcome assessments, the quality of the conduct of the study (e.g. loss to follow up and success of blinding), absolute and relative size of any effects seen etc. are known to affect the quality of evidence. [36] This means that conclusions drawn from the SRs in terms of some products have "been tested in robust clinical studies and found effective"[22] needs to be cautiously interpreted. Application of risk of bias tool was also inappropriate in Das et al. [20] This review reported quality or risk of bias as "moderate degree as most were open label trials" by using the Cochrane Risk of Bias tool–without providing any further information. The Cochrane tool assessed a trial with ratings for low risk, high risk or uncertain risk for each of the six separate domains without a composite degree of bias being evaluated for individual RCTs. [37] Where quality of reported studies was mentioned, certainty of the effect estimates for different interventions included in the SRs varied but were almost never of high quality. Accounting for the impact of risk of bias of included primary studies in the results of the synthesis and accounting for it while interpreting the results of the SR would enable more informed decision in the future.
The current study also highlights two important aspects with respect to the completeness of the available evidence at the systematic review–there are many important interventions and outcomes on snakebite management on which SRs have not been conducted, and, for when they have been done, apart from quality of SR, there is need to update them. A full discussion on these aspects comprehensively is beyond the scope of the current study and the need for future work to guide this has been discussed subsequently. Broadly, some domains on which primary research evidence exists but no SR available or there is need for update available ones are—wound management, managing psychological impacts, role of antibiotics, interventions for preventing adverse reaction due to SAV and effectiveness of SAVs. [38–43]
Potential biases in the overview process
The overview includes SRs irrespective of study design, recognising the fact that randomised evidence for snakebite envenoming might be difficult to generate. We used a comprehensive search strategy that was implemented in multiple electronic databases. Screening, data extraction and quality assessment using AMSTAR-2 was done by at least two study authors independently with discrepancy being resolved by consensus. As such, high rigor has been maintained in the overview process. The only limitation of our overview is that its broad scope has meant that we had to depend on the findings of SRs on varied topics without any consistent methods of reporting.
Implications for practice, policy and research
With the development of WHO strategy and the goal to reduce death and disability due to snakebite envenomation to half by 2030, accentuated attention. [8] In our previous work, we evaluated WHO guidelines on snakebite envenomation and found limited use of available evidence in formulating recommendations and heavy reliance on expert opinion. [9] The current work highlights the challenges in formulating high quality evidence informed guidelines owing to the lack of high quality SRs. As such, the lack of high-quality SRs on snakebite is a critical gap which needs attention from global health funders. High-quality SRs and other evidence synthesis which can aid clinical and public health decision making and appropriate investments can guide future primary research too. Given the paucity in primary research evidence, conduct of RCTs and its resourcing is also needed. Developing an evidence gap map of RCTs for snakebite envenomation might be the first step towards this purpose to enable set research priorities. Our overview also indicated the lack of consistency in defining and measuring outcomes for snakebite envenoming. Standardisation on what outcomes are measured and how they are measured will enable comparison between different interventions and ensure relevance for different stakeholders including patients. There is a tremendous need for development of a core outcome set [44] for clinical studies on snakebite. The variation in species distribution as well as intra-species variation in venom composition implies the need for conduct of region, nation or state (sub-national) specific RCTs and SRs on different SAVs and their dosing regimens. The results of this overview can inform priorities for funding and conduct of high-quality SRs and other evidence synthesis on management of snakebite envenomation. Key considerations for practice, policy and research and policy is summarised in Box 1.
Box 1: Key considerations for practice, policy and research
- High quality systematic reviews to inform clinical practice guidelines do not exist. There is no strong evidence to either support or refute many interventions related to snakebite envenomation.
- Investments in "research on research" and evidence synthesis including conduct of high-quality systematic review, development of intervention evidence gap map, and development of core outcome sets on snakebite envenomation might help inform research policy and practice better.
- Systematic reviews on snakebite envenomation should follow high quality standards to enable critical assessment of existing evidence base for development of clinical practice guidelines.
- Systematic reviews on snakebite should extract snake-species specific data whenever reported. Even if species disaggregated outcome data is not reported in the primary studies, sub-group analysis might provide potentially useful information.
- Randomised controlled trials, providing evidence on effectiveness and safety of different snake anti-venoms specific in different geographic settings and for specific snake-species is a gap that needs to be addressed. Such trials should minimally use core-outcome sets to enable wider utility.
- Funding high quality randomised controlled trials addressing existing clinical issues on first-aid, different snake anti-venoms, preventing adverse drug reactions, and wound management for snakebite envenomation is a priority area that needs to be addressed.
Ensuring safe, effective treatments which can bring down the burden of snakebite requires conduct of high-quality SRs. The lack of high-quality SRs hampers guideline development as well as informing priorities for primary research on snakebite.
Supporting information
S1 Table. PRISMA Checklist for Interventions for the management of snakebite envenoming: an overview of systematic reviews.
S2 Table. Reasons for exclusion in full-text phase for Interventions for the management of snakebite envenoming: an overview of systematic reviews.
S1 Text. Search Strategies for Interventions for the management of snakebite envenoming: an overview of systematic reviews.
The authors would like to acknowledge the peer-reviewers for the valuable comments which has enriched the manuscript.
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Rafael Nadal knew: 'Carlos Alcaraz has a great potential'
by JOVICA ILIC | VIEW 5475
Rafael Nadal and Carlos Alcaraz met for the first time in Madrid last year. The more experienced Spaniard earned a commanding 6-1, 6-2 victory over the rival who celebrated the 18th birthday on that day. Carlos became one of the youngsters to watch since the season's restart in August 2020, claiming three Challenger titles and moving closer to a place in the top-100.
Alcaraz qualified for the Australian Open at the beginning of 2021 and became the youngest player with a Major win since 2014. A teenager reached the Marbella semi-final and scored his first Masters 1000 victory in Madrid against Adrian Mannarino.
Carlos earned a bagel in the second set and got a chance to play against his idol Rafael Nadal on his 18th birthday. The youngster could not do much against the mighty opponent, experiencing an injury in the early stages and playing way below his best.
Rafa lost serve once and turned over 60% of the return points into five breaks. Nadal hit 13 winners and eight unforced errors and took advantage of almost 30 unforced errors from an 18-year-old to race into the last 16.
Rafael Nadal honored his young compatriot Carlos Alcaraz after their Madrid clash.
Carlos made a strong start in the first game and earned a break chance.
Rafa saved it and closed the game with a service winner. Nadal forced the rival's error in the second game to grab the first break before Carlos experienced that injury a few minutes later. Rafa won the third game with a volley winner and seized another break for a 4-0 advantage.
The more experienced Spaniard held at love in game five with an incredible forehand down the line winner and held at love with a service winner two games later to wrap up the opener in 36 minutes. Continuing where he left, a five-time Madrid Open champion scored two breaks at the beginning of the second set and forged a 3-0 lead before Alcaraz pulled one break back to reduce the deficit and show the fighting spirit.
In game five, Rafa placed a perfect return winner for a break at love and crossed the finish line with a smash winner at 5-2 on his third match point. Praising his young compatriot, Rafa said that Carlos has a massive potential to carry him towards the top in the upcoming years.
Nadal was not wrong, and Alcaraz is already on the verge of the top-15, still before the 19th birthday. "Carlos has massive potential. He is young, dedicated and a good guy. He already has an excellent level of tennis today, and I believe that he will be a fantastic player soon.
I wish him all the very best. As a Spanish player and Spanish tennis fan, we need someone like Carlos, and it's great to have him here," Rafael Nadal said.


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August Doesn't Matter?
by Patrick Appel
That's Michael Scherer's take after reading a new poll that shows little movement on public support of health care:
What matters is what happens in September and through the fall. Will Obama get Republican support? (On this point, the right wing backlash, especially to the degree it impacts people like Sen. Chuck Grassley, matters a great deal.) Will he be able to pass meaningful reforms? (Including ones that liberals cheer, and industry lobbyists decry.) Will be be able to pass anything? By the time we learn the answers to these questions, the August excitement is likely to seem little more than a distant dream.
There is a problem with this line of thought: arguments that make it outside of the beltway need to be seeded early and have plenty of time to incubate. The debates of August will mutate into the debates of September and beyond. That is why the primary attacks against Obama and McCain were seeded months and months before the election.


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Labor Day is around the corner, signaling the unofficial end of summer and the start of a new school year. This is your last chance to have some summer fun! Avoid long lines or flight delays at the airports and take your family or friends on a fun road trip.
Renting a Statevan's passenger van is the perfect transportation for your end-of-the-summer adventure. Our spacious van allows you to travel together with your friends, keep the children from kicking each other, or give you more room for camping gear while saving you money and wear-and-tear on your car.
If you're traveling with a large group, our 15-passenger van rental in Los Angeles is the perfect choice for your trip. Smaller groups may benefit from renting a 12-passenger van in LA.
You won't be able to escape the heat, so head up to San Francisco on the Pacific Coast Highway (PCH) and enjoy the scenic coastal route and the cool ocean breeze. There are plenty of quaint towns where you can watch the marine wildlife, wine taste, or hike.
About Pacific Coast Highway (PCH)
Before we get started on the must-see places, the PCH has a few nicknames. Today, South Californians know PCH as the "One," but it began as Route 60 and then was named the Roosevelt Highway, after Theodore Roosevelt, when it opened in the late 1920s. Throughout the years, PCH has been called Route 3, Route 101 Alternate, and California State Route 1 in 1964. Today, the PCH's nicknames are Highway One, the Cabrillo Highway, the Shoreline Highway, the Redwood Highway, etc. To avoid confusion, it is never called the 101, which is an entirely different highway but does overlap the PCH several times.
Here are our ideas for the best places to stop on the Pacific Coast Highway:
- Los Angeles to Santa Barbara
- Santa Barbara to Solvang
- Solvang to Paso Robles
- Paso Robles to Big Sur
- Big Sur to Monterey
- Monterey to San Francisco
Whether you have one week off or just the holiday weekend, choose your own adventure but be sure to enjoy the marine wildlife, a glass of wine at a winery, and soak in the stunning coastal lines.
Los Angeles (Santa Monica) to Santa Barbara
Estimated Driving Time: 2.5 hours
Head to Santa Monica in the morning and start your road trip to Santa Barbara on the PCH. Santa Barbara is a mix between a Mediterranean city and an American city between the Santa Ynez Mountains and the Pacific Ocean. Don't miss the Old Mission Santa Barbara, the 10th and best-preserved California Missions founded by the Spanish Franciscans in 1786. You can still see the influence of the 300 years of Spanish colonial rule, which lasted until 1822 with the conclusion of the Mexican War of Independence. Santa Barbara became a part of the expanding United States in 1848 as a result of the Mexican-American War.
We recommend grabbing an early lunch at Santa Barbara's most famous restaurant, La Super-Rica Taqueria on Milpas Street. It's a casual and budget-friendly eatery that Isidoro Gonzalez founded in 1980. The authentic, flavorful Mexican food made the late Julia Child a regular.
If you have extra time, you can check out the city's stunning panoramic 360-degree view at the Santa Barbara County Courthouse's clock tower or take a stroll down Stearns Wharf and soak in the beautiful beach view.
Santa Barbara to Solvang
Estimated Driving Time: 40 minutes
After lunch in Santa Barbara, take a detour to Solvang, a charming Danish Village founded by Danish settlers in the early 1900s. It is the most unique town you will see on your road trip. Solvang is known for its windmills, gorgeous Danish architecture, tasty Danish pastries, and of course, their wine and craft beer. Check out one of more than a dozen wine tasting rooms.
If you are traveling with children, you should swing by Ostrichland where you can see emus and ostriches up close and feed them.
Solvang to Morro Bay:
Estimated Driving Time: 1.5 hours
Paso Robles is about a 48-minute drive from the PCH, but it is an excellent mid-point to stop overnight. Before you head inland to Paso Robles, stop by Morro Bay. Morro Bay is a tourist destination that was founded in 1870 as a port for the export of dairy and ranch products. Today, it is a marine wildlife sanctuary, and there are always sea lions and harbor seals that make the docks their nap spots. You can also spot otters along its Embarcadero. The best time to catch them is 8 or 9 in the morning near the dock next to the Great American Fish Company, but you might get lucky in the late afternoon. Otherwise, you can stay overnight in Morro Bay and skip Paso Robles to get a glimpse of the otters, but don't worry, you will be able to see more otters in Monterey.
Morro Bay's main highlight is Morro Rock, a giant volcanic plug sitting at the coast's edge along the bay. The volcanic plug is a chain of nine volcanic mountains in San Luis Obispo County. In the past, the rock has acted as a natural beacon for seafarers as early as the 1500s and was considered sacred ground to the Chumash and Salinan native tribes.
If you have more time, hike up the Black Hill, a moderate 2.5-mile back trail that offers 360-degree views of downtown Morro Bay or rent a kayak to get up close to the marine life.
If you plan to stay overnight in Morro Bay, we recommend having early dinner at the local's favorite restaurant, Tognazzini's Dockside Too. This casual seaside restaurant has gorgeous ocean views and the freshest and most delicious fish in town.
Morro Bay to Paso Robles:
Estimated Driving Time: 45 minutes
After 16 miles or so back on the PCH, you will see a sign for Paso Robles/CA-46. Turn right to head inland, into wine country, Paso Robles. The 46 is a beautiful stretch of highway that cuts through chaparral and grass-covered rolling hills. About 6.5 miles down the road, you'll reach the apex of the hill; look to the right, and you'll see Green Valley Viewing Point, an observation point that offers a breathtaking view of the surrounding hills.
Paso Robles has the perfect weather for wine-making. The region began grape growing in 1797, and now there are more than 200 wineries, 26,000 vineyard acres, and 40 varietals of wine, but they are known for their Zinfindel, Cabernet, and Rhone blends. Here is a helpful site that filters out the wineries to your liking and your company; just because you are traveling with children, it doesn't mean you can't go wine tasting. A favorite family-friendly winery is Riverstar Vineyards. You can also go beer tasting at one of the six breweries in Paso Robles.
For lodging, the Paso Robles Inn is conveniently located in the center of downtown Paso Robles, within walking distance of the best restaurants and tasting rooms. Check reviews or book at Booking.com.
We recommend La Cosecha, a popular family-owned farm-to-table Latin-inspired flavor restaurant offering tapas to pizzas for dinner. For breakfast, Andrea's on Pine has a lovely outdoor patio and delicious quiche and French toast.
If you have extra time, saddle up and see the rolling California countryside on a horse with Central Coast Trail Rides or discover wine country up in the air by ziplining at Margarita Adventures. Margarita Adventures have six ziplines, starting with a 2,800-foot tandem-line thrill ride and finishing with a 1,800-foot journey over Pinot Noir vines. It's the perfect adventure for the thrill-seekers, but please zip line before you go winetasting!
Paso Robles to San Simeon
Estimated Driving Time: 45 minutes
The must-visit place in San Simeon is the famed newspaper tycoon William Randolph's, Hearst Castle. Unfortunately, the roadway leading up to the Castle is severely damaged and it will be closed for six to nine months. However, for those who enjoy quirky architect, the "Anti-Hearst Castle," best known as the Nitt Witt Ridge, is open just right off the PCH in Cambria. Arthur "Art" Harold Beal bought the land in 1928 and spent the next fifty years creating his own "castle on a hill" with whatever material he can find –from beer cans, and driftwood to parts of the Hearst Castle.
Whether you are an adult or traveling with children, the Elephant Seal Vista Point is a must pit-stop before heading up to Big Sur. The cliff overlooks an elephant seal rookery with the world's largest population of Northern Elephant Seals and can be seen throughout the year. From the Elephant Seal Rookery, you will be able to see Piedras Blancas Light Station. If time permits, take a tour of the Light Station.
San Simeon to Big Sur
Estimated Driving Time: 1 hour & 20 minute
The Big Sur has jaw-dropping ocean views along the highway and countless State Parks just waiting to be explored. The best State Parks along the Big Sur are Julia Pfeiffer Burns State Park, Pfeiffer Beach, the Limekiln Beach State Park, and Andrew Molera State Park. For outdoors lovers, be sure to spend at least a full day at one of Big Sur's California State Parks for fantastic hiking and some serious natural beauty, but make sure the trails are open. If your time is limited, be sure to stop by at the iconic McWay Falls, one of California's two tide falls, at the Julia Pfeiffer Burns State Park. You can park on the main highway road and save money and walk down to the viewing spots for the falls. Pfeiffer Beach is part of the Los Padres National Forest and is famous for having a big rock with a hole that looks like a cavern. It is a popular spot, so it is best to get there early to find parking because you cannot park along the road.
We also recommend you to take a pit stop at the Bixby Creek Bridge, one of the area's most iconic photo spots. Head north on the PCH for about 11 miles, and you will notice a ton of people pulled over on the north side of a bridge. The Bixby Creek Bridge was a Depression-era work project and was completed in 1932.
Restaurant options are scarce here, but we recommend Big Sur Bakery which offers high-quality baked pastries, or a local barbecue spot Big Sur Smokehouse.
Big Sur to Monterey:
Estimated Driving Time: 1 hour
After the Bixby Creek Bridge, continue north on the PCH, and you will see two attractions before arriving at Monterey.
For outdoor lovers, a hike in Point Lobos Natural Reserve is a must. The reserve has miles of looping trails with killer cliff-side views and resident sea lions. Go early or late because they have tiny parking lots, or you can save state park fees by parking on the main road and walk-in.
When you finish your hike, continue on the PCH for another 16 miles, and you will arrive at the beginning of the 17 Mile Drive. This popular private scenic road follows the coastal route between Pacific Grove and Carmel. You will pass the coastal cliff and the iconic Lone Cypress at Pebble Beach and its golf course. The entrance fee is $10.50 per car.
Continue on the stunning coastline to Monterey, famous for its year-round whale watching and its world-class aquarium. The bay is a national marine sanctuary that houses a wide range of marine diversity, including; humpback, Orca and blue whales, sea otters, great white sharks, harbor seals, sea lions, and three kinds of dolphins. Whale watch costs around $60 per adult. Go to Metatrip to find the most affordable tour.
Another boat tour worth considering is with Elkhorn Slough Safaris. They will take you up the river estuary to see otters, seals, sea lions, and sea birds.
The Monterey Bay Aquarium is the most famous in the United States, and it continues to inspire visitors and conservationists more than 30 years after its opening. Nearly 200 permanent exhibits introduce visitors to 35,000 creatures of over 550 species, a compelling reminder of our profound connection to the oceans. The aquarium's sea otter and penguin shows are wildly popular. The show put on by the playful animals as they are fed and put through training exercises by expert aquarists is a big reason the aquarium is the number one attraction on the Monterey peninsula. You don't want to miss out on encountering a glowing jellyfish at the Jellies.
Don't forget to learn about Monterey's rich history. Founded in 1770, Monterey had functioned as the capital of Alta California, under both Spain (1804-1821) and Mexico (1822-1836). The city hosted California's first theater, public building, public library, publicly funded school, printing press, and newspaper, but it was made famous by the local darling literary giant John Steinbeck in his novels Cannery Row and Tortilla Flat. It is worth checking out Monterey's Path of History, a free self‐guided tour of Old Monterey, marked by easy‐to‐distinguish yellow tiles set on the sidewalk.
If you are exhausted from all the walking, stay in and have a pizza from Pizza My Heart deliver to your hotel room, or if you still have energy, have dinner at the local craft brewery and restaurant, Alvarado Street Brewery & Grill's outdoor patio.
In the morning, head over to the 3 Mundos Sandwich Shop for an inexpensive, tasty breakfast burrito, or you can order their famous Argentine Trip Tip sandwich for lunch before getting back on the road. Another breakfast or lunch option is Poppy Hall in Pacific Grove, offering classic comfort food.
Monterey to San Francisco:
Estimated Driving Time: 2 hours
In a couple of hours, you will reach your final destination, San Francisco, one of the most iconic cities in the world. San Francisco is often thought of as the technology hub of America, but its legacy is the revelatory architecture and its rich history –from the Gold Rush to the "hippie" countercultures, the Sexual Revolution, the Peace Movement, and establishing the first LGBTQ neighborhood in the country. The city is full of vibrant neighborhoods, parks, beaches, museums, and a whole host of entertainment options and things to do for you to explore. And you will eat your heart out at some of San Francisco's most dynamic food scenes, from humble Mission District burrito joints to Michelin-starred dining rooms.
Before you tour the city, we recommend parking your vehicle at your lodging location as it's pretty convenient for you to get around. Just be sure to bring all valuable belongings inside.
The most iconic landmark in San Francisco is the Golden Gate Bridge. Connecting San Francisco with Marin County, the Golden Gate Bridge is the most photographed site in the city and was, at one time, designated the extraordinary man-made sight in the United States by the U.S. Travel Service. The bridge only took four years to build, and it opened on May 28th, 1937. If you want to drive over the Golden Gate Bridge, the road is US Hwy 101, or SR 1, and there is a toll fee. The walkways on either side of the bridge are open to pedestrians and cyclists and free, but it is only open during daylight hours. The walk begins at the start of the bridge (accessible from the Presidio shuttle) and ends with a viewpoint in Marin County. Many locals enjoy biking across the bridge to the nearby waterfront town of Sausalito. The city offers free walking tours on Thursdays and Sundays. Battery Godfrey offers a stunning view of the Golden Gate Bridge. You can take more picturesque photos of the Golden Gate Bridge from Crissy Field, a grass field, and a sandy beach with a restored marsh.
From Crissy Field, it's an easy walk to the Palace of Fine Arts, the last remaining structure from the 1915 Panama Pacific Exposition. Listed on the National Register of Historic Places, this classical-looking building is beautifully situated on a lagoon that reflects the mirror image on the surface of the calm water while ducks and geese drift. Today, the Palace hosts art exhibitions and performances.
Make your way over to Fisherman's Wharf and Pier 39. Fisherman's Wharf is one of San Francisco's most lively tourist areas. This old section, once the Little Italy of San Francisco, has over 50 stores and unique places to eat and is known for its beautiful setting along the waterfront. It's a fun place to stroll around and get a taste of the city. The docks by pier 39 are some of the best areas in the city to see sea lions.
From Pier 33, you can catch a ferry to Alcatraz Island and visit the historic and notorious Alcatraz prison, where some of America's most well-known criminals were inmates here, including Al Capone. It operated for almost thirty years, closing in 1963 and re-opening as a tourist attraction in 1973. While most people come for the history or the novelty of seeing a former prison, the island is now a prominent area for nesting seabirds. If you are short on time, an easy, convenient way to see Alcatraz and some of the other highlights of San Francisco, like Fisherman's Wharf, Chinatown, and the Golden Gate Bridge, is to take a combined Alcatraz and San Francisco City Tour. Alcatraz regularly sells out, so booking in advance is strongly advised.
Once you're done with the tour, make your way to North Beach, otherwise known as Little Italy. North Beach has historically been home to a large Italian population as well as the center of the beatnik subculture. Today, the neighborhood is one of San Francisco's central nightlife districts and has many Italian restaurants. Tony's Pizza has excellent Neapolitan-style pizza, and you get it by the slice or order a whole pie.
Adjacent to North Beach is Chinatown, the largest and oldest Chinatown outside of Asia. Almost completely destroyed in the 1906 earthquake, Chinatown was rebuilt entirely in the Chinese style and was soon even more attractive than before the disaster. With its temples, theaters, restaurants, antique and souvenir shops, teahouses, and traditional pharmacies, visiting Chinatown has become one of the top things to do in San Francisco. For tourists, the main street in Chinatown is Grant Avenue, with the Chinatown Gateway at Grant Avenue and Bush Street. If you are craving Chinese, dine at the iconic Sam Wo Restaurant, serving authentic Chinese cuisine since 1908. George Chen's China Live is another good option.
Take advantage of the city's free walking tours in each neighborhood, architect, and landmark. You can make reservations on their site.
No trip to San Francisco is complete without riding San Francisco's historic cable cars. Cable Cars were introduced in 1873 to help locals contend with the many hills the city is built on. Today, the few remaining cable cars offer tourists a great way to explore the city in a historic fashion. Since 1964, these tram-like vehicles have had the unique distinction of being the only public transport system to be declared a historic monument. Tickets can be purchased on board the cable car, or if you are planning on more than a couple of rides, consider buying a pass. If time permits, check out the Cable Car Museum; it's free!
For art lovers, the San Francisco Museum of Modern Art (SFMOMA) is one of the city's top museums, with 170,000 square feet of exhibition space spread across ten floors. The museum focuses on 20th-century art in all forms, and the innovative and exciting exhibits are constantly changing. The permanent collection consists of 33,000 pieces, and one of the more interesting collections is contained within the Fisher Collection.
If you have more time, drive down Lombard Street, the 'Crookedest Street' of San Francisco. You will start at the top of Lombard and slowly wind your way down while appreciating the beautiful flowers.
If you have more time, take a day trip up to the two best-known and largest grape-growing areas, Napa Valley and Sonoma Valley. It is just 1.5 hours north of San Francisco. The area is incredibly scenic, with a drier climate than the coastal regions. It was founded in 1848 and bears the name of the long-extinct Napa Indians. The western boundary is formed by the Napa Mountains. The Howell Mountains form the eastern boundary of Napa County, and they also protect the valley from storms.
Things to bring:
- Binoculars
- Warm clothes –the coast can get very cold and windy
- Umbrella, hat, sun glasses
- Charger for your phone and iPad
- Water, snacks, Ziploc bags, utensils
- Bug sprays
- Car phone charger
- Hand sanitizer, trash bags, wipes, toilet paper
- A roll of quarters
- Hand lotion, chapstick, sunscreen
- First Aid Kit, aspirin
- Travel pillow
- Whether it is lodging, restaurants, or tours, make reservations in advance. It's a holiday weekend!
- Be sure to check your gas gauge. There are stretches of hours before coming across a gas station. If you are unsure, fill up the tank to be on the safe side. This also applies with the bathroom break, and don't forget to pack a toilet paper roll.
- Again, don't leave any valuable things in the vehicle at all times.
- Dispose of your trash properly. The majority of the coastline is made up of fragile ecosystems. Do your part to stop erosion and damage by not going somewhere dangerous and staying on the trails.
- Before you get on the road, check the weather to see if there are any road closures.
- State Van offers Electronic Toll Pass, so you don't have to worry about getting a ticket.
Make Your Reservation With State Van Rental Today
We at State van wish you and your family and friends a safe and fun Labor Day! For all your van rental needs please call us.


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OPINION by CYNTHIA REPLOGLE Since I joined the Oceano Community Services District (OCSD) Board in 2018, I've been working to make our meetings more accessible and inclusive. I firmly believe in participatory democracy and that government bodies should always act... (Continue reading)
OPINION by DREW VAN DUREN An open letter to the San Luis Obispo County Board of Supervisors: The unscrupulous cannabis hijack of the Board of Supervisor's Dec. 17 public comment period served only to 1) avoid conforming cannabis operations with... (Continue reading)
OPINION by ANDY CALDWELL I identified as a traditional democrat for half my life because then and now, I wanted the little guy to have a fighting chance! This has to do with my life experience. I grew up relatively... (Continue reading)
OPINION by RICHARD SCHMIDT San Luis Obispo is going to save the earth from global warming. In 15 years. Faster than anybody – including the state of California or the United Nations — thought possible. We're going to do it,... (Continue reading)
OPINION by JULIE TACKER The factual inaccuracies in the latest San Luis Obispo New Times Shredder column titled "Drama machine," show a desperate attempt to produce drama and a failure to accurately report the news. While trying to draw a... (Continue reading)
OPINION by JULIE TACKER Merry Christmas Los Osos. Here we go again, prepare yourselves for coal in your stocking as the San Luis Obispo County Board of Supervisor will raise garbage rates by 25.31 percent, both inside and outside the... (Continue reading)
OPINION by ANDY CALDWELL Something happened that has caused me to do something I never intended to do, and that is declare my candidacy to be your representative in Congress. It all has to do with Ronald Reagan's famous words,... (Continue reading)
Opinion by James Lopes, an open letter to the San Luis Obispo City Council I recently learned that my affordable housing neighbors are being slapped with 300 percent plus rent increases, right before the holidays. They live in an "affordable"... (Continue reading)
Opinion by Peter Keith, an open letter to State Parks I am the former mayor of Grover Beach, and current 'charter member' of the Technical Review Team (TRT), which reports to various state agencies including State Parks and the California... (Continue reading)
OPINION by JULIE TACKER The Arroyo Grande City Council voted to increase their monthly stipends by sixty percent! On top of that, they agreed to award the mayor an additional $150 per month. It is their intention that these increases... (Continue reading)


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February is the month of love, the month where many people celebrated being able to be together and share so many special moments; It is the month where friends celebrate the friendship of years, admiring each other every day. Now, it's not just about receiving but giving ourselves with unequaled appreciation.
Where to go, where to take that special other? This Sunday 16th you have the opportunity, the ideal place to: "Fall in Love with Tango", through the presentation of Oscar López Salaberry, from 7:30 pm and precisely, at "Restaurante Atocha Don Bosco", located 50 meters west from the Church of Don Bosco, in front of the Grano de Oro Hotel, San José.
TIP: Get updates on upcoming Costa Rican Retreats & Events by joining our newsletter. Don't miss out on what's happening around you! Click here.
Also, you can enjoy exclusively the former ambassador of Argentina in Costa Rica, who plays the bandoneon and saxophone, accompanied by guitarist "Roberto Antillón" along with the "Divas of Tango". It will be an unforgettable evening, with a repertoire of Tangos, Milongas and course melodies of love and heartbreak. The Dance Hall will be open all night.
What is the purpose of this event … Beyond letting you spend a magical evening enjoying wonderful moments with special people, the purpose is also to generate cultural entertainment on Sundays, which includes music, humor and other performing genres.
With ample parking space for your car and the option to book by phone: 2220-0207.
Sundays in Costa Rica will not be the same again, they will be pure entertainment and enjoyment!


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A vacant supermarket in Clonmel has become the stage for an exciting theatrical production 'Everything Must Go'.
Market Place's former Superquinn was acquired by Supervalu before finally closing its doors to the public in 2016.
The building has now reopened for an interactive theater experience inspired by the region's urban decline.
Produced by Asylum Productions, Once Off Productions and Clonmel Junction Festival, the production written by Aideen Wylde and Donal Gallagher creates an immersive and unique theatrical experience.
Audiences are encouraged to engage in the haunting wasteland and walk the abandoned alleys as the actors provide simultaneous performances.
The eclectic ensemble of ghostly figures are performed by a mix of professional and local amateur actors.
Memorable acts include a haunting dance by cashiers and a butcher wandering the aisles with a cart adorned with human limbs.
Lighting by Declan O'Sullivan alongside sound composition design by Dave Boyd helps transform the vast building, brilliantly creating the illusion of separate compartments for the audience to explore.
Music from old advertisements helps to create a haunting nostalgia, with empty shelves prompting audiences to reflect on our society's addiction to excess consumption.
One particularly clever aspect of the production is how it uses the original features of the vacant building to add to the production.
The supermarket's preserved aisles are still adorned with old price tags and old customer notices are a stunning addition to Medb Lambert's vibrant design.
Features like the clinical meat prep area, the haunting candle-lit bakery, and the storage room adorned with a spooky Christmas display add to the unsettling nature of the surreal performances.
Auctioneers encourage the public to bid on the empty building, their presence compared to flies on a corpse in the once bustling shopping district.
What could have been a rambling production is brought together by a moving musical finale with moving choreography by Cindy Cummings.
The play helps the audience imagine what it would be like to buy groceries after an atomic bomb was dropped on O'Connell Street.
Far from a traditional trip to the theater, the opportunity to enjoy the interactive and free nature of this production is not to be missed.