The systematic search identified potentially relevant citations. Following application of the inclusion and exclusion criteria, 44 articles were eventually selected and the full manuscripts were reviewed. The selection process is illustrated in Figure 1. Twelve publications were case-controlled studies on bicarbonate administration versus no bicarbonate in DKA. Of these, two studies were nonblinded randomized controlled trials RCT [ 13 , 14 ], and one study was a double-blind RCT [ 15 ].
A total of 73 adult patients were included in these three RCTs. The remaining nine studies were nonrandomized, prospective, or retrospective studies, which include six adult studies [ 16 — 21 ], two involving both adult and pediatric patients [ 22 , 23 ], and one pediatric study [ 24 ].
In addition, four pediatric nonrandomized prospective and retrospective studies investigated the association between bicarbonate administration in DKA and risk of CE [ 25 — 28 ]. There were no similar studies in the adult DKA cohort. In Table 1 we summarized the threshold for bicarbonate administration in various studies, which includes the initial degree of acidemia and base deficit [ 4 , 13 — 24 , 29 — 36 ].
Dosing methods vary widely with study design and physician preference, and these are summarized in Table 2. Concentrated bicarbonate dosing based on calculations using predictive formulas incorporating base deficit [ 37 , 38 ] results in a tendency for over-correction and alkalosis [ 29 , 30 ]. Aiming for a more modest and intermediate pH target with bicarbonate dose less than half of that predicted, or dose titrated based on pH severity, were some of the variable approaches adopted subsequently by investigators [ 4 , 23 ].
One single-center retrospective pediatric study assessed duration of hospitalization as an outcome measure [ 24 ]. Duration of hospitalization was significantly longer 87 vs. However, there was no adjustment for confounding variables. Bicarbonate therapy did not seem to have an impact on duration of hospitalization. Therefore, there may be a weak association with prolonged hospitalization in children with DKA treated with additional bicarbonate therapy, but the evidence is of very poor quality.
No published trials on the use of bicarbonate therapy in DKA were able to comment on any mortality difference with or without its use.
Critically ill DKA cases with severe metabolic acidemia were excluded from most studies. Eight case-control studies have examined the rates of acidosis reversal with or without additional bicarbonate therapy, including three RCTs. The results are summarized in Table 3. Improvements in pH and serum bicarbonate levels were used as markers of acidosis reversal [ 13 — 15 , 17 — 20 , 24 ].
Two adult RCTs demonstrated biochemical benefit in terms of acidosis reversal time, with improved pH and bicarbonate levels at 2 hours of therapy in the bicarbonate arm. Of these, one study administered isotonic bicarbonate as a slow infusion [ 13 ], whereas the other administered small intermittent bicarbonate boluses of higher concentration titrated to severity of pH [ 15 ].
The latter study extended the follow-up duration to 24 hours of therapy and did not find a sustained biochemical benefit beyond 2 hours. A third adult RCT administered similar incremental small boluses of sodium bicarbonate but did not establish a similar biochemical advantage [ 14 ]. In addition, three retrospective adult studies [ 17 , 18 , 20 ] and one retrospective pediatric study [ 24 ] showed no improvement in acidosis resolution with use of bicarbonate therapy.
As shown in Table 3 two adult studies showed paradoxical worsening of ketonemia, including a slower decline in ketonemia in the first hour of bicarbonate infusion in a RCT [ 13 ], and an increase in plasma acetoacetate levels during the initial three hours of bicarbonate infusion in a small, prospective, nonrandomized study [ 19 ].
Results of pediatric and adult studies that reported insulin sensitivity and glycemic control as outcome measures are summarized in Table 4.
No significant difference in rate of glucose decline or insulin requirement was demonstrated with bicarbonate treatment. Seven studies examined potassium balance as an outcome measure and are summarized in Table 5. Four other studies including one pediatric study did not detect any statistical difference in the potassium balance [ 14 , 17 , 18 , 24 ].
A mixed adult and pediatric, three-arm prospective study, examined the association between mean cumulative bicarbonate doses and potassium requirement. The two groups that received saline and low-dose bicarbonate mean mmol had comparable potassium supplementation during first 24 hours, whereas the third group with high bicarbonate dose mean mmol received higher potassium supplementation [ 22 ]. One adult RCT reported a significantly slower rate of decline in blood lactate and lactate to pyruvate ratio in the bicarbonate treatment arm, compared with saline control, in the first hour of treatment in DKA [ 13 ].
A slow decline in blood lactate to pyruvate ratio was used to imply tissue hypoxia. Bicarbonate therapy was not shown to affect oxygen transport adversely [ 16 ]. One adult RCT performed CSF analysis in approximately half of the adult patient cohort to investigate the concern of paradoxical CSF acidosis with bicarbonate administration.
The study did not find any statistically significant difference in CSF pH and bicarbonate levels within 24 hours in the bicarbonate-treatment group and control. However, patient numbers were small, and a trend for larger decline in CSF pH at 6 to 8 hours was observed in the bicarbonate group [ 14 ].
In another nonrandomized study, the study subjects who received additional bicarbonate therapy for DKA [ 23 ] were compared with controls from an older study, which used the usual treatment with insulin and saline [ 39 ].
The possible association of bicarbonate therapy with the development of CE in DKA was highlighted in three nonrandomized studies that investigated risk factors for CE in pediatric DKA patients Table 6.
Glaser et al. Bicarbonate therapy was the only treatment variable associated with a greater risk of CE, after comparing with matched controls. The relative risk was 4. Comparable proportions of children in the CE group and matched control had bicarbonate infused within 2 hours before neurological deterioration; hence no bias was detected [ 25 ].
Two other smaller studies found a trend for bicarbonate use and an association with CE, but the risk was not significant after adjusting for covariates, including baseline acidosis [ 26 , 27 ].
A fourth pediatric study demonstrated that impaired conscious level in DKA was associated with younger age and lower initial pH, and CE cases had lower pH compared with matched controls with no CE, at every conscious level studied [ 28 ].
Three adult studies have examined neurological recovery as a secondary outcome. One RCT examined mental status at 0, 2, 6, 12, and 24 hours after therapy, and found no difference in both treatment arms [ 15 ]. Two other retrospective studies also found no difference in neurological status with bicarbonate therapy, in patients with varying degrees of impaired mental status at baseline [ 18 , 20 ].
There were no pediatric studies on neurological recovery. None reported any difference in clinical parameters with or without added use of bicarbonate [ 15 , 18 , 20 ].
We conducted a systematic review of the literature, comparing additional use of bicarbonate infusion versus the usual treatment with insulin and hydration, in pediatric and adult patients with DKA.
We have found marked heterogeneity and no clear evidence, with regards to the threshold for, concentration, amount, and timing of bicarbonate administration. In addition to such variability of treatment, there was retrospective evidence of clinical harm, such as increased risk for CE and prolonged hospitalization in children, and weak evidence of physiological harm, such as transient paradoxical worsening of ketosis and increased need for potassium supplementation.
Theoretical benefits perceived with rapid acidemia reversal were not evident, apart from weak evidence of transient improvement in acidosis, with no evidence of any clinical efficacy. The primary cause of acidemia in patients with DKA is ketoacidosis, with contribution from lactic acidosis and renal dysfunction. It was observed and suggested in these studies that hyperchloremic acidosis is likely contributed by preferential renal excretion of ketones over chloride anion and volume repletion with saline, with the most rapid rise in hyperchloremia coinciding with the period of greatest saline administration [ 43 ].
Theoretically, adjunct use of bicarbonate administration may be more beneficial in the scenario of reduced renal bicarbonate genesis with concomitant acute kidney injury or in hyperchloremic acidosis where there is deficiency of bicarbonate relative to chloride.
Although bicarbonate therapy in DKA has been shown in two RCTs to improve acidosis resolution in the initial few hours of therapy, the comparator consisted of sodium chloride infusion. Thus, the initial favorable physiologic outcome with bicarbonate therapy might represent a reduced risk of hyperchloremic acidosis.
Despite so, patient numbers were small, and this transient physiological benefit had not been demonstrated to persist beyond the initial 2 hours. Concerns were raised that bicarbonate therapy might interfere with tissue oxidation and with the clearance or renal excretion of ketones, hence accounting for the paradoxical worsening of ketosis.
Severe acidosis may inhibit the action of insulin on glucose utilization. Insulin resistance in humans has been shown to be higher at lower pH range and resistance to fall steeply at pH above 7. Early and rapid correction of acidemia can theoretically increase insulin sensitivity. However, as discussed, there is no evidence of the above-postulated benefit of bicarbonate therapy. Instead, lower serum potassium and increased need for potassium supplementation had been demonstrated by mainly adult studies, including one small RCT, in the bicarbonate treatment arm.
Although no fatal outcomes or arrhythmias had been reported as a result of hypokalemia, it would be prudent to pay close attention to this anticipated complication. Acute reversal of acidemia with bicarbonate also has been linked to worsening of tissue hypoxia.
Acidosis induces a mild increase in P 50 and reduced hemoglobin-oxygen affinity Bohr effect , but at the same time is associated with lower levels of 2,3-diphosphoglycerate 2,3-DPG in erythrocytes [ 45 ], which leads to a counteractive increased hemoglobin-oxygen affinity.
In the initial presentation of DKA, a fine balance exists in favor of the former Bohr effect [ 16 ], which can theoretically be disrupted by rapid treatment of acidemia, as 2,3-DPG levels were demonstrated to remain strikingly low for days despite improvement in acidosis [ 46 ], resulting in net increase in hemoglobin-oxygen affinity and impaired tissue oxygenation. However, this phenomenon is generally seen in the initial treatment phase of DKA, regardless of bicarbonate therapy.
P 50 , along with blood lactate to pyruvate ratio, are merely surrogate markers of peripheral tissue oxygenation used in studies.
Therefore, there remains to be insufficient evidence that additional bicarbonate administration affects tissue oxygenation adversely. Bicarbonate therapy in patients with DKA appeared to be associated with increased obtundation and profound cerebrospinal fluid CSF acidosis in an early study [ 47 ].
A possible explanation for this observation may be the preferential movement across the blood-brain barrier of CO 2 compared with bicarbonate during treatment of DKA, when both P CO2 and bicarbonate levels rise in the blood. It was postulated that rapid reversal of acidemia with bicarbonate might promote paradoxical CSF acidosis and contribute to adverse neurological outcomes.
However, we have not found any evidence that bicarbonate infusion causes increased paradoxical CSF acidosis compared with conventional DKA treatment. In essence, most of the theoretical biochemical gains and harm with bicarbonate administration were not evident in actual case scenarios, and the overall physiological impact with such treatment is dismal.
The pathophysiology of CE remains unclear, and a detailed discussion on this is beyond the scope of this article. Ann Pharmacother The following two tabs change content below. Bio Latest Posts. Latest posts by Darrel Hughes see all.
Like this article? Share on facebook Share on Facebook. Share on twitter Share on Twitter. Share on linkedin Share on Linkdin. Share on email Share via Email. Want to support rebelem? Ad space. Yes the ADA which is older guidelines does recommend bicarb at Reply. Been told bicarb amp if ph was that low and about to intubate to help maintain. Salim Reply. Appreciate you reading and great point about the crashing patient Salim Reply.
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