Letter to the Editor: “Plasma alkalinization for acute organophosphorus poisoning – is it a reality in the developing world?”

To the Editor:

We read with interest the recent publication describing the effect of high dose intravenous sodium bicarbonate (NaHCO₃) in the management of acute organophosphorus (OP) pesticide poisoning (1). The authors should be congratulated on completing this study which has made an important contribution to the literature. Although their study suggested favourable outcomes from NaHCO₃, the authors recommended that studies with larger numbers are still required. The World Health Organization has also highlighted the potential efficacy of NaHCO₃ as an antidote for OP poisonings, recommending further research (2).

As a prelude to conducting a trial, we conducted a systematic review through the Cochrane Collaboration to assess the evidence supporting this treatment (3). While concluding that there was insufficient evidence to recommend the routine use of plasma alkalinization for acute OP poisoning, we also identified that research was required to determine the method and regimen of alkalinization to optimally induce and maintain the target arterial pH. As efficacy appears likely to be dose related (1,4), dose-finding studies need to precede any randomized controlled trials that might convincingly prove or disprove the efficacy of plasma alkalinization.

We would like to inform readers of some of the problems we encountered when trying to conduct a dose-finding study in a large rural hospital in Sri Lanka. Approval was obtained from ethics committees at Anuradhapura General Hospital, the University of Colombo, and Australian National University. Local physicians were supportive of the study and co-investigators. However, problems with finding a simple and practical protocol that could be conducted in a developing world rural hospital prevented research into this antidote from progressing.

The first problem arose with a planned intravenous bicarbonate study. As in Balali-Mood's study, our initial plan was to administer intravenous NaHCO₃ in doses aimed to a target pH of 7.50 (range 7.45–7.55). A variable dosing regimen seemed necessary to allow dose-titration so that the target pH would be maintained until recovery, to cater for the metabolic and/or respiratory compensation that would be expected from administration of NaHCO₃ continuously over a number of days, and to prevent over-alkalinization. We intended to use an established formula for correction of the base-deficit (5) based on frequently repeated arterial blood gases.

The logistics of frequently monitoring plasma arterial pH, necessary in terms of both safety and efficacy also proved difficult. Indwelling arterial lines are not usually available in general hospitals in Sri Lanka given the lack of equipment, staff trained in their use, and sterility concerns. Since it is undesirable to obtain repeated arterial blood samples due to pain and an increased risk of vessel damage, including occlusion with distal ischaemia, we conducted an arterial-venous blood gas correlation study to determine the venous pH and bicarbonate concentration which corresponded to target arterial values. This demonstrated the feasibility of using repeated venous blood gas sampling from an indwelling cannula in this setting to monitor pH.

However, concerns remained regarding the safety of plasma alkalinization with intravenous NaHCO₃. In particular, the potential for fluid overload (including pulmonary oedema) was raised because of case reports in the literature from regimens using larger fluid volumes for forced alkaline diuresis. This hospital, like many secondary referral hospitals in Sri Lanka, has very limited resources in terms of monitored beds in the ICU or wards, and very high patient-physician and patient-nurse ratios. Therefore, there was concern that adverse reactions such as fluid overload may have a severe outcome. The treating physicians were not prepared to accept these risks.

We changed to an oral dosing regimen of NaHCO₃, given that volunteer studies had indicated that this route of administration was sufficient to induce plasma alkalinisation (6). However, the revised study protocol was also unable to be implemented. The first few patients with OP poisoning enrolled in the study found the taste of the oral NaHCO₃ solution (made from NaHCO₃ powder mixed with water and various flavouring agents) extremely unpleasant and frequently led to vomiting. This was confirmed in volunteers from the investigators. Since it is not routine to insert nasogastric tubes in all patients with acute OP poisoning and alternative oral formulations (e.g., capsules) were unavailable in Sri Lanka, the study was terminated.

The study by Professor Balali-Mood et al. involved repeated arterial blood sampling and administration of intravenous NaHCO₃. It was conducted in an Intensive Care Unit in a tertiary referral hospital where sufficient resources were available for patient monitoring. As highlighted above, these resources are not widely available in Sri Lankan hospitals. It is likely that our experiences will not differ to those of other peripheral hospitals in developing countries where OP poisonings are common.

If more research on the effect of intravenous NaHCO₃ for the management of acute OP poisoning is to be conducted in hospitals in developing countries, additional safety data are required. We would be interested to hear of Professor Balali-Mood et al.'s experiences with safety and efficacy of their fixed “high dose” regimen of 5mEq/kg loading, then 5-6mEq/kg/day until recovery or death. Specifically, we welcome more information on whether this regimen maintained the target plasma pH (7.45 – 7.55) for the duration of the admission, and how often dose reduction or increases were necessary, and when over the course of the illness these dose adjustments needed to be made. In terms of safety, we are interested in the incidence and extent of over-alkalinization (pH>7.55) and whether hypercarbia (e.g., pCO₂>55mmHg) was noted more often in patients receiving NaHCO₃. Further, clarification of the incidence of fluid retention (with or without pulmonary oedema) and electrolyte changes (particularly hypernatremia, hypokalemia, or hypocalcemia) post-admission would be useful. Such data might convince local physicians that intravenous bicarbonate therapy can be given safely in this setting, and also help others planning future trials that may be conducted in centres similar to our study hospitals in Sri Lanka.